Articoli di riviste: "He53"

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Kent, Matthew R., Delia Calderon, Katherine M. Silvius, Jack P. Kucinski, Collette A. LaVigne, Matthew V. Cannon e Genevieve C. Kendall. "Abstract 3533: Zebrafish her3 knockout impacts developmental and rhabdomyosarcoma-related gene signatures". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 3533. http://dx.doi.org/10.1158/1538-7445.am2023-3533.

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Abstract HES3 is a basic helix-loop-helix transcription factor that regulates neural stem cell renewal during development. HES3 overexpression is predictive of reduced overall survival in patients with fusion-positive rhabdomyosarcoma, a pediatric cancer that resembles immature and undifferentiated skeletal muscle and is most commonly driven by the fusion-oncogene PAX3-FOXO1. However, the mechanisms of HES3 cooperation in PAX3-FOXO1 driven rhabdomyosarcoma are unclear and are likely related to her3/HES3’s role in neurogenesis. To investigate HES3’s function during development, we generated a zebrafish CRISPR/Cas9 null mutation of her3, the zebrafish ortholog of HES3. Phenotypic characterization revealed that her3 null mutation is not embryonic lethal as they are present at expected Mendelian ratios. We observed a temporary growth delay her3 zebrafish null mutants and, rarely, eye defects in adults. Transcriptomic analysis of her3 null mutant embryos showed early dysregulation of a known downstream target, neurog1 and downregulation of genes involved in organ development, such as pctp and grinab, while genes pointing toward a terminal differentiation state, such as tmod, are upregulated. Differentially expressed genes in her3 null mutant embryos are enriched for HOX and SOX10 motifs, suggesting these may be key genes involved during HES3 dysregulation. Several cancer-related gene pathways are impacted, including the inhibition of matrix metalloproteinases and the tumor microenvironment pathway. To complement our zebrafish model, we are developing a double-inducible cell line model consisting of a tetracycline-inducible HES3 and a cumate-inducible PAX3-FOXO1 to further investigate the hypothesized cooperation between her3/HES3 and PAX3-FOXO1 in fusion-positive rhabdomyosarcoma. These two systems will allow us to elucidate conserved mechanisms of cooperation between HES3 and PAX3-FOXO1, and identify new therapeutic opportunities for children with fusion-driven rhabdomyosarcoma. Citation Format: Matthew R. Kent, Delia Calderon, Katherine M. Silvius, Jack P. Kucinski, Collette A. LaVigne, Matthew V. Cannon, Genevieve C. Kendall. Zebrafish her3 knockout impacts developmental and rhabdomyosarcoma-related gene signatures. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3533.

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Beckford Vera, Denis, Jason Li, Le-Cun Xu, Debbie Lewis, Amanda Chin, Patrik Brodin, Mary Chen, Monideepa Roy e Helen Kotanides. "Preclinical evaluation of novel HER3-targeting radioconjugates for the imaging and treatment of HER3-expressing cancers." Journal of Clinical Oncology 41, n. 16_suppl (1 giugno 2023): e15114-e15114. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e15114.

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e15114 Background: HER3 overexpression in tumors is associated with poor survival and is implicated in drug resistance mechanisms of HER1 (EGFR) and HER2 targeted therapies. Although antibodies against HER3 have been developed and evaluated in clinical trials, no HER3 targeted therapy has been approved, underscoring the unmet need for novel HER3 therapeutic approaches. We hypothesized that HER3 radioligand targeted therapies could provide enhanced therapeutic efficacy against HER3-positive cancers through the energy deposited by alpha or beta emitting radionuclides in tumor cells. Here we describe the development and preclinical evaluation of novel anti-HER3 antibody radioconjugates (ARCs), 225Ac-HER3 and 177Lu-HER3, using the alpha-emitting Actinium-225 (225Ac) and beta-emitting Lutetium-177 (177Lu) radioisotopes, respectively. Methods: ARCs were prepared by radiolabeling HER3 antibody with 225Ac or 177Lu using S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA) to yield 225Ac or 177Lu-HER3-ARCs. DOTA modified antibodies were characterized by HPLC and MALDI-TOF and HER3-ARCs were fully characterized by instant thin-layer chromatography (iTLC) and HPLC. The in vitro binding properties of the HER3-ARCs were evaluated using HER3 recombinant proteins and cells expressing HER3 in ELISA and flow cytometry. The in vivo pharmacological properties of the HER3-ARCs were evaluated by molecular imaging using Zirconium-89 (89Zr) Positron Emission Tomography (PET), biodistribution and antitumor efficacy studies. Results: HER3 antibody was successfully modified with p-SCN-Bn-DOTA to yield a conjugate with approximately 8 DOTAs per antibody molecule. Results from the in vitro binding assays of ARCs to either HER3 human recombinant protein or cells expressing HER3 demonstrated similar binding properties of 225Ac-HER3 and 177Lu-HER3 to unmodified HER3 antibody. The biodistribution study in NCI-H1975 tumor bearing mice showed that both 225Ac-HER3 and 177Lu-HER3-ARCs specifically accumulate in HER3-expressing tumors relative to other tissues. In agreement with the biodistribution studies, PET images revealed specific uptake of 89Zr-HER3 in NCI-H1975 tumors. Furthermore, 225Ac and 177Lu-HER3-ARCs showed significantly more potent NCI-H1975 tumor growth inhibition compared to controls. Conclusions: Our findings suggest that a HER3 targeted radiotherapy approach can enhance therapeutic response and overcome the limitations of previously explored HER3 targeted drug modalities. Thus, further preclinical evaluation of 225Ac-HER3 and 177Lu-HER3 is warranted, including in settings of tumor drug resistance, which can provide the basis for investigating HER3-ARCs as an effective treatment approach in future clinical trials.

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Koyama, Kumiko, Hirokazu Ishikawa, Manabu Abe, Yoshinobu Shiose, Suguru Ueno, Yang Qiu, Kenji Nakamaru e Masato Murakami. "Patritumab deruxtecan (HER3-DXd), a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against breast cancer cells expressing HER3 mutations with and without HER2 overexpression". PLOS ONE 17, n. 5 (3 maggio 2022): e0267027. http://dx.doi.org/10.1371/journal.pone.0267027.

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ErbB3 (HER3), a member of the HER family, is overexpressed in various cancers and plays an important role in cell proliferation and survival. Certain HER3 mutations have also been identified as oncogenic drivers, making them potential therapeutic targets. In the current study, antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate, was evaluated in tumor models with clinically reported HER3 mutations. MDA-MB-231, a HER3-negative human triple-negative breast cancer cell line, was transduced with lentiviral vectors encoding HER3 wild type (HER3WT), one of 11 HER3 mutations, or HER3 empty vector (HER3EV), in the presence/absence of HER2 overexpression. Targeted delivery of HER3-DXd was assessed using cell-surface binding, lysosomal trafficking, and cell-growth inhibition assays. HER3-DXd bound to the surface of HER3WT and mutant cells in a similar, concentration-dependent manner but not to HER3EV. HER3-DXd was translocated to the lysosome, where time- and concentration-dependent signals were observed in the HER3 mutant and HER3WT cells. HER3-DXd inhibited the growth of HER3WT and HER3 mutant cells. HER3-DXd activity was observed in the presence and absence of HER2 overexpression. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation.

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Komatsu, Nagiho, Saori Sato, Sumie Muramatsu, Ryuichi Nakamura e Kumiko Koyama. "Abstract 3996: The impact of HER3 dynamics on the efficacy of HER3-DXd, a novel HER3 directed antibody-drug conjugate". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 3996. http://dx.doi.org/10.1158/1538-7445.am2023-3996.

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Abstract Background: HER3 is broadly expressed in various solid tumor types, and its expression can be upregulated by treatment with receptor tyrosine kinase inhibitors (RTKi) such as EGFR TKIs used to treat EGFR-mutated NSCLC. HER3-DXd, a novel antibody-drug conjugate (ADC) composed of a human anti-HER3 IgG1 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload (DXd), is currently being studied in clinical trials for breast cancer and NSCLC. As previously reported, HER3-DXd treatment transiently decreases HER3 expression levels in tumors and EGFR TKIs increase HER3 membrane expression. However, the impact of HER3 dynamics on payload delivery has not been clarified yet. In this study, we investigated HER3 dynamics including HER3 receptor turnover and payload delivery in cancer cells using HER3-DXd both as a single agent and in combination with RTKi including osimertinib, which is in clinical trials in combination with HER3-DXd. Methods: HER3/ADC internalization was evaluated by using confocal imaging in MDA-MB-453 cells treated with HER3-DXd. Internalization and payload release were quantitatively measured in 3 cancer cell lines treated with HER3-DXd. HER3 turnover on the cell surface was also evaluated upon wash-out of HER3-DXd. In xenograft models, mice were administered two doses of HER3-DXd at different doses and dosing intervals, and membrane HER3 expression and tumor payload concentration were examined over time. NSCLC cell lines harboring EGFR activating mutations, ROS1 fusions, or ALK fusions were used to evaluate the effect of osimertinib, lorlatinib, or ceritinib on cell surface HER3 expression and payload release (osimertinib only). Results: HER3-DXd was rapidly transferred to early endosomes after binding to HER3. HER3 dynamics varied among the cell lines tested in vitro, and payload release reflected cell surface HER3 expression levels, HER3 internalization speed and turnover rates. In xenograft models, a higher dosage of HER3-DXd resulted in a larger decrease in membrane HER3 expression. Dosing interval also affected membrane HER3 expression levels; the degree of tumor payload concentration increase after the second dose was dependent on the recovery of HER3 expression after the first dose. Furthermore, we confirmed that RTKi increased the cell surface HER3 expression in NSCLC cell lines with targetable driver genomic alterations and that osimertinib increased payload delivery in PC-9 cells through the upregulation of cell surface HER3 expression. Conclusion: HER3 expression was dynamically changed by HER3-DXd dosing regimen and by RTKi treatment, resulting in a substantial impact on payload release. These findings support our strategy of clinical studies using HER3-DXd after drugs that increase HER3 expression including EGFR TKI and indicate that HER3 dynamics may play a key role in achieving optimal efficacy of HER3-DXd. Citation Format: Nagiho Komatsu, Saori Sato, Sumie Muramatsu, Ryuichi Nakamura, Kumiko Koyama. The impact of HER3 dynamics on the efficacy of HER3-DXd, a novel HER3 directed antibody-drug conjugate. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3996.

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O'Hare, Thomas, Jaclyn Cleveland, Valerie M. Jansen e David Dornan. "Abstract 3121: Therapeutic potential of a HER3 antibody-drug conjugate for the treatment of HER3-expressing cancers". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 3121. http://dx.doi.org/10.1158/1538-7445.am2024-3121.

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Abstract To address the need for targeted therapy in the treatment of HER3-positive solid tumors, the human HER3 mAb, seribantumab, was evaluated in the context of an antibody-drug conjugate (ADC). As a proof-of-concept, seribantumab was conjugated with a cleavable valine-citrulline linker and monomethyl auristatin E (MMAE) payload via the stochastic cysteine conjugation method to yield HER3-ADC1. A drug-antibody ratio of 4 was selected for preclinical assessment in HER3-expressing models. Methods: HER3-ADC1 was evaluated in vitro and in vivo, with patritumab deruxtecan (patri-DXd) as a comparator. Binding to BT474 breast carcinoma cells (HER3 high; immunohistochemical (IHC) staining intensity 3+) was measured by flow cytometry. Internalization properties were established using seribantumab and patritumab coupled to Fab-AF488 following 4 hours incubation in SK-BR-3 breast adenocarcinoma (HER3 high; IHC 3+) and HCC1569 breast carcinoma (HER3 low; IHC 0-1+) cell lines. In vitro cytotoxicity was evaluated for HER3-ADC1, isotype-MMAE and free MMAE payload as well as patri-DXd, isotype-DXd and free deruxtecan payload in BT474 cells, SK-BR-3 cells and NCI-H446 lung carcinoma (HER3 low; IHC 0-1+) cells. In vivo anti-tumor activity was assessed for HER3-ADC1, isotype-MMAE, patri-DXd and isotype-DXd in patient derived xenograft (PDX) models of pancreatic (HER3 high; IHC 3+) and breast cancer (HER3 low; IHC 0-1+). Results: HER3-ADC1 binding to cancer cells, endocytosis, MMAE release, and inhibition of proliferation were dependent on HER3 expression. In assays investigating antibody internalization, seribantumab displayed similar internalization capacity as patritumab. For both HER3 mAbs, internalization was greater in a HER3 high than a HER3 low cell line. In cytotoxicity assays, HER3-ADC1 and patri-DXd displayed HER3 expression level-dependent cell killing. HER3-ADC1 outperformed patri-DXd in HER3 high cell lines based on in vitro cytotoxicity. HER3-ADC1 and patri-DXd were ineffective against NCI-H466 cells with low HER3 expression. In a PDX model of pancreatic cancer (HER3 high), HER3-ADC1 induced tumor regression, while isotype-MMAE had only a moderate anti-tumor effect. Both patri-DXd and isotype-DXd had moderate anti-tumor effects, indicating a lack of HER3 target dependence. In a PDX model of breast cancer (HER3 low), HER3-ADC1 and isotype-MMAE lacked anti-tumor activity; isotype-DXd had a moderate anti-tumor effect and patri-DXd had a substantial anti-tumor effect. Conclusions: HER3-ADC1 demonstrated target-dependent in vitro cytotoxicity and in vivo anti-tumor activity in a HER3-expressing pancreatic cancer PDX model. Results from in vitro and in vivo studies highlight the promising therapeutic potential of a seribantumab-based ADC for patients with HER3-expressing cancers. Additional results on the optimization and characterization of HER3-ADC1 will be presented. Citation Format: Thomas O'Hare, Jaclyn Cleveland, Valerie M. Jansen, David Dornan. Therapeutic potential of a HER3 antibody-drug conjugate for the treatment of HER3-expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3121.

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Beckford-Vera, Denis, Megan McCloskey, Jason Li, Caroline Jennings, Le-Cun Xu, Debbie Lewis, Patrik Brodin et al. "Abstract 5040: Novel HER3 targeting antibody radioconjugates, 225Ac-HER3 ARC and 177Lu-HER3 ARC, exhibit potent antitumor efficacy in HER3-positive solid tumors". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 5040. http://dx.doi.org/10.1158/1538-7445.am2023-5040.

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Abstract Background: HER3 is a unique member of the EGFR family that collaborates with other EGFR receptors to induce tumorigenesis and drug resistance. Moreover, HER3 expression is linked to poor survival for patients with solid tumors. Despite HER3 being a rational cancer therapeutic target, no HER3-directed therapies have been approved for clinical use. However, new therapeutic strategies such as antibody drug conjugates (ADCs) are being investigated. Targeted radiotherapy, including radiolabeled antibodies (ARCs), is unique mechanistically by inducing cell death independent of biologic pathway inhibition, and can be efficacious with less toxicity relative to other therapeutic modalities. Therefore, we hypothesized that the cytotoxic effects of alpha (225Ac) or beta (177Lu) emitting radionuclides combined with the specificity of anti-HER3 antibody targeting is a compelling therapeutic approach for HER3-expressing tumors. Here we evaluated the antitumor effects of 225Ac or 177Lu armed HER3 ARCs across multiple HER3-expressing cancer models such as ovarian, colorectal, prostate, and renal cancer. Methods: ARCs were prepared by radiolabeling AT-02, an anti-HER3 antibody, with 225Ac or 177Lu using p-SCN-Bn-DOTA to yield 225Ac or 177Lu-HER3 ARC. The binding activity and tumor cell cytotoxicity of HER3 ARCs were assessed by ELISA using human recombinant HER3, flow cytometry on HER3-expressing cells, and colony forming assays. To evaluate the antitumor growth effects of 225Ac-HER3 and 177Lu-HER3 ARCs in vivo, preclinical human tumor xenograft models were developed. Mice bearing HER3-positive tumors were dosed with 225Ac-HER3 ARC (0.2 or 0.4 µCi), or 177Lu-HER3 ARC (200 or 400 µCi) and tumor growth and body weight was monitored. Results: The pharmacological binding properties of HER3 antibody radiolabeled with 225Ac or 177Lu were similar to that of unmodified antibody as demonstrated by HER3 binding ELISA and flow cytometry. HER3 ARCs induced cytotoxicity and inhibited colony formation of HER3-positive tumor cell lines. Significant in vivo human tumor xenograft growth inhibition was observed in response to 225Ac or 177Lu HER3 ARCs compared to control groups (unmodified AT02 or IgG ARCs) in the models studied. No significant loss of body weight was observed in mice treated with HER3 ARCs suggesting that all treatments were well tolerated. Conclusions: In this study, both 225Ac-HER3 ARC and 177Lu-HER3 ARC demonstrated significant antitumor activity against HER3-expressing tumors in a dose-dependent manner. The HER3 targeted radiotherapy approach that we have undertaken could potentially overcome the limitations of current solid tumor therapies in resistance settings and warrants further evaluation in patients with HER3-expressing tumors. Citation Format: Denis Beckford-Vera, Megan McCloskey, Jason Li, Caroline Jennings, Le-Cun Xu, Debbie Lewis, Patrik Brodin, Amanda Chin, Monideepa Roy, Mary Chen, Helen Kotanides. Novel HER3 targeting antibody radioconjugates, 225Ac-HER3 ARC and 177Lu-HER3 ARC, exhibit potent antitumor efficacy in HER3-positive solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5040.

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Toy, Weiyi, Dipti Thakkar, Roberto Magallanes, Sharon Wu, Ming Poi, Alejandro Mas, Konrad Paszkiewicz, Piers Ingram e Jerome Boyd-Kirkup. "Abstract 5796: A HER3 antibody that uniquely blocks the HER3 heterodimerization interface effectively inhibits tumor growth in pre-clinical models with potentially oncogenic HER3 mutations". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 5796. http://dx.doi.org/10.1158/1538-7445.am2024-5796.

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Abstract HER3 activation, via NRG1 ligand-dependent and -independent heterodimerization with HER2 or EGFR, has been associated with tumor progression and acquired resistance to therapies in multiple indications. HER3 mutations, detected in around 3% of cancer cases, may drive oncogenic signaling, leading to rapid tumor growth. Currently, there are no approved targeted therapies for HER3 mutations. Through analysis of real-world data and structural modelling of HER3 heterodimers, we identified four common HER3 mutations located within or close to the dimerization interface of HER3, suggesting a potential impact on HER3 heterodimerization. Immunoprecipitation assays confirmed that all four mutations increased the heterodimerization of HER3 with both HER2 and EGFR. Further, conversion of an endogenous HER3 mutation to wild type via CRISPR editing significantly reduced the growth of KYSE-150, a HER3 mutant cell line. HMBD-001 is a clinical-stage anti-HER3 antibody rationally developed to uniquely block the HER3 dimerization interface to potently inhibit HER3 heterodimerization. Through structural analysis and FACS binding on HER3 mutation cell lines, we confirmed that the binding epitope of HMBD-001 does not overlap with the selected HER3 mutations and therefore may be a good therapeutic option for patients with HER3 mutations. In vitro, HMBD-001 suppressed HER3 mutation-driven PI3K/AKT signaling, as demonstrated by the reduction of phosphorylated HER3 and AKT levels. In multiple cell- and patient-derived xenograft models with HER3 mutations HMBD-001 response achieved >80% tumor growth inhibition. Based on this encouraging preclinical data, a Phase Ib clinical trial (NCT05919537) has been initiated, evaluating HMBD-001 in patients with aberrant HER3 signaling, including HER3 mutations. Citation Format: Weiyi Toy, Dipti Thakkar, Roberto Magallanes, Sharon Wu, Ming Poi, Alejandro Mas, Konrad Paszkiewicz, Piers Ingram, Jerome Boyd-Kirkup. A HER3 antibody that uniquely blocks the HER3 heterodimerization interface effectively inhibits tumor growth in pre-clinical models with potentially oncogenic HER3 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5796.

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Beckford-Vera, Denis, Jason Li, Megan McCloskey, Caroline Jennings, Amanda Chin, Qing Liang, Jesse Hwang, Monideepa Roy, Mary Chen e Helen Kotanides. "Abstract 3306: Targeting HER3 receptor positive cancers with a novel anti-HER3 antibody radioconjugate (ARC)". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 3306. http://dx.doi.org/10.1158/1538-7445.am2022-3306.

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Abstract Background: HER3 overexpression is reported to be associated with poor survival in breast, ovarian, lung, gastric and prostate cancer. In addition, upregulation of HER3 in response to HER1 or HER2 targeted therapies, is implicated in the acquired resistance against these therapies. Therefore, effective targeting of HER3 can potentially overcome resistance and enhance therapeutic efficacy. Although a number of anti-HER3 antibodies have failed clinical testing with the development focus being shifted to other approaches such as antibody drug conjugates and bispecific antibodies, there are currently no approved HER3-targeted therapies. Here we describe a novel approach that can enhance therapeutic efficacy in HER3+ cancer patients by conjugating an anti-HER3 antibody with the alpha-emitting cytotoxic radioisotope Actinium-225 (225Ac) to create an anti-HER3 antibody radiation conjugate (225Ac-HER3-ARC). Alpha emitting radioisotopes like 225Ac can cause double-strand DNA breaks for which there is no known resistance mechanism. Due to the cytotoxic properties of the radioisotope, lower levels of antibody may be needed, resulting in reduced incidence or less severe toxicities. We hypothesize that targeting HER3 in solid tumors with an ARC will result in tumor specific cell killing especially in a setting where HER-targeting agents are not a viable option. We developed a novel 225Ac-HER3-ARC and evaluated its efficacy in HER3+ in vitro and in vivo tumor models. Methods: AT-02, an anti-HER3 antibody, was conjugated with p-SCN-Bn-DOTA and radiolabeled with 225Ac. 225Ac-HER3-ARC specific binding to HER3 was assessed by ELISA using human recombinant HER3 and by flow cytometry on HER3+ cells. The cytotoxic effect of HER3 ARC was evaluated in a panel of HER3 expressing cells. We further evaluated the maximum tolerated dose and therapeutic efficacy of the ARC in nude mice bearing human HER3+ xenograft tumors. Results: In this study we successfully radiolabeled anti-HER3 with 225Ac. 225Ac-HER3-ARC showed similar binding properties to those of the native antibody by ELISA (HER3-ARC: EC50 = 0.0017 µg/ml, HER3 EC50 = 0.0022 µg/ml) and flow cytometry. Treatment with ARC was cytotoxic to HER3+ cells in a dose-dependent manner (EC50 = 54 kBq/ml). 225Ac-HER3-ARC showed potent in vivo efficacy in preclinical solid tumor xenograft models that was correlated with the in vitro cytotoxicity findings. Treatment with 225Ac-HER3-ARC (7.4 - 22.2 kBq, 200 - 600 nCi) led to complete responses and significantly prolonged survival compared to control groups (p < 0.0001). Conclusions: Our findings demonstrate that targeting HER3 with a novel 225Ac-HER3-ARC results in potent tumor cell cytotoxicity and complete anti-tumor response in HER3 tumor xenograft model. This approach provides a promising therapeutic strategy for HER3 positive tumors and warrants further assessment. Citation Format: Denis Beckford-Vera, Jason Li, Megan McCloskey, Caroline Jennings, Amanda Chin, Qing Liang, Jesse Hwang, Monideepa Roy, Mary Chen, Helen Kotanides. Targeting HER3 receptor positive cancers with a novel anti-HER3 antibody radioconjugate (ARC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3306.

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Scartozzi, M., A. Mandolesi, R. Giampieri, A. Zaniboni, E. Galizia, L. Giustini, R. R. Silva, R. Berardi, I. Bearzi e S. Cascinu. "The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan/cetuximab." Journal of Clinical Oncology 29, n. 4_suppl (1 febbraio 2011): 404. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.404.

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404 Background: Preclinical data suggested that in presence of HER3 altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. HER3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER3 expression and clinical outcome in KRAS wild-type advanced colorectal cancer receiving cetuximab and irinotecan. Methods: We retrospectively analyzed immunoreactivity for HER3 in KRAS wild-type advanced colorectal cancer patients receiving irinotecan-cetuximab. Results: Eighty-four advanced KRAS wild- type colorectal cancer patients were available for HER3 analysis. Forty patients (48%) showed HER3 negative colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER3 positive. In HER3 negative and HER3 positive tumors we observed a partial response in 17 (42%) and 8 (18%) patients respectively (p = 0.04). Progressive disease was obtained in 11 (35%) and 26 (53%) patients with respectively HER3 negative and positive tumor (p = 0.007). No differences were observed for stable disease. Median PFS was 6.3 months in patients showing HER3 negative tumors and 2.8 months for those who had HER3 overexpressing tumors (p < 0.0001). Median overall survival was 13.6 months in patients showing HER3 negative tumors and 10.5 months for those who had HER3-expressing tumors (p = 0.01). Conclusions: HER3 proved to be a predictive factor for clinical outcome in KRAS wild-type colorectal cancer patients treated with cetuximab. Combined HER3 and KRAS analysis may represent an effective strategy for a better selection of responding colorectal tumors. Furthermore besides identifying colorectal cancer patients refractory to EGFR directed treatment, HER3 overexpression may also represent a potential biological indicator for the development of a new class of antineoplastic agents in this setting. No significant financial relationships to disclose.

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Martinez Lago, Nieves, Ihab Abdulkader, Dora Insua Santamaria, Patricia Viaño Nuñez, Juan Jose Carrera, Jose Ramón Antunez Lopez, Maria Elena Padin Iruegas e Rafael López López. "Assessment and prognostic impact of a new classification using HER2 and HER3 status in resected gastric cancer in a european cohort." Journal of Clinical Oncology 36, n. 4_suppl (1 febbraio 2018): 65. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.65.

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65 Background: HER2 status is a predictive biomarker to response to trastuzumab in metastatic gastric adenocarcinomas. However, relatively little is known about the role of HER2 and HER3 in the non-metastatic disease in European population. Methods: Immunohistochemical expression of HER2 was analyzed using DAKO-HercepTest™ and gene amplification using DAKO-DuoCISH kit; both was scored according to published reports. HER3 expressión was analyzed using HER3 clon DAK-H3-ICHER3 and scored as follows: 0 = no staining, 1+ = light staining, 2+ = moderate staining, and 3+ = strong staining. Slides with score 0 or 1+ were classified as low expression or negative and slides with score 2-3+, as high expression or positive. According HER2 and HER3 status patients were classified into six subtypes: HER2-HER3 negative, HER2 equivocal expression HER3 negative, HER2 positive – HER3 negative, HER2 negative – HER3 positive, HER2 equivocal expression – HER3 positive and HER2-HER3 positive. The relationship between this classification and the clinicopathological characteristics and survival was analyzed retrospectively. Results: We included 106 patients between January 2007 and June 2014. The HER2 positivity was 13.2% and HER3 high expression was identified in 27.4% of patients. HER2 status was significantly associated with HER3 status (p = 0.018). HER2 equivocal or positive subtypes were associated with intestinal subtype (0.020) and HER2 or HER3 positive subtypes were associated with low histological grade (0.050). Our classification have demonstrated prognostic impact (p = 0.032) with a specific mortality rate due to gastric cancer of 45-50% for patients with equivocal or positive HER2 subtypes with HER3 low expression, 30% for patients with HER3 high expression independently of HER2 status, and 18% for patients HER2-HER3 negative. Conclusions: Our classification, using HER2 and HER3 status, stratifies patients into 6 subtypes with differentiated clinical and pathological characteristics and prognostic impact.

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Mukherjee, Sumit, Debbie Lewis, Jason Li, Le-Cun Xu, Amanda Chin, Mary Chen, Monideepa Roy et al. "Abstract A149: Characterization of HER3 targeted radioligand therapy using molecular imaging". Molecular Cancer Therapeutics 22, n. 12_Supplement (1 dicembre 2023): A149. http://dx.doi.org/10.1158/1535-7163.targ-23-a149.

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Abstract Background: Radioligand therapy (RLT) is an emerging treatment modality that has shown potential to improve survival in cancer patients that often have limited or non-effective therapeutic options. We previously demonstrated that anti-HER3 antibody radioconjugate (HER3 ARC) has antitumor efficacy against HER3 expressing tumor xenograft models. One important step in the early development of RLT is to understand the targeting properties and the distribution of the RLT in vivo. Non-invasive molecular imaging such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer unique opportunities to understand drug behavior in vivo, permitting real time drug targeting and distribution analysis. In this study, we assessed the targeting properties and distribution of our HER3 ARC in HER3 expressing preclinical xenograft tumor models using both SPECT and PET. Methods: HER3 monoclonal antibody was conjugated with p-SCN-Bn-deferoxamine (DFO) or p-SCN-Bn-DOTA (DOTA) then labeled with Zirconium-89 (89Zr) or Indium-111 (111In), respectively. Flow cytometry and gamma counting was used to characterize HER3 ARC biological activity in HER3-expressing tumor cell lines. Balb/c mice subcutaneously inoculated with HER3-expressing xenograft tumors (lung, ovarian and colorectal) were intravenously administered with 89Zr-DFO-HER3 or 111In-DOTA-HER3. PET or SPECT scans were acquired 72 and 120-144hrs post injection of the radiotracer. Separate cohorts of mice were simultaneously administered with 89Zr-DFO-HER3 or 111In-DOTA-HER3 and 20-fold excess of native HER3 antibody as control to block radiotracer binding. Tissue uptake was quantified by drawing 3D or 2D regions of interest (ROI) for PET or SPECT images, respectively. Results: HER3 ARC radiotracers were successfully prepared and demonstrated similar binding to HER3 expressing cells compared to native HER3 antibody. In tumor-bearing mice, 89Zr-DFO-HER3 and 111In-DOTA-HER3 specifically accumulated in HER3 expressing tumors and cleared throughout the reticuloendothelial system. High tumor uptake was observed 120hrs post radiotracer injection using both imaging modalities. In mice pre-treated with 20-fold excess of native antibody, tumor uptake was significantly lower, showing tumor binding specificity of ARC. PET and SPECT images showed similar tracer distribution profile in the HER3 tumors. As expected, radiotracer clearance organ signals were also visualized. Conclusions: In this study we show that PET or SPECT imaging using 89Zr or 111In, respectively, offers the potential to assess the distribution of HER3 targeted radioligand therapy during early stages of drug development. HER3 ARC showed highly specific HER3 tumor uptake that remained at least 120hrs post injection. Our findings warrant further investigation to support advancement of HER3 ARC as a therapeutic option. Citation Format: Sumit Mukherjee, Debbie Lewis, Jason Li, Le-Cun Xu, Amanda Chin, Mary Chen, Monideepa Roy, Patrik Brodin, William van der Touw, Helen Kotanides, Denis Beckford-Vera. Characterization of HER3 targeted radioligand therapy using molecular imaging [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A149.

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Xie, Xuemei, Jangsoon Lee, Jon A. Fuson, Huey Liu, Young Jin Gi, Pang-Dian Fan, Kumiko Koyama, Debu Tripathy e Naoto T. Ueno. "Abstract LB088: Targeting ATR enhances the antitumor efficacy of patritumab deruxtecan (HER3-DXd) in tamoxifen-resistant ER+ breast cancer cells by reprogramming cell cycle progression". Cancer Research 82, n. 12_Supplement (15 giugno 2022): LB088. http://dx.doi.org/10.1158/1538-7445.am2022-lb088.

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Abstract Background: HER3, a member of the ErbB family of receptor tyrosine kinases that activate multiple oncogenic signaling pathways, is overexpressed in 50-70% of breast cancers (BC). HER3 mRNA levels are higher in ER+ breast tumors than in other molecular subtypes. Inhibition of ER activity using an antagonist increased HER3 protein expression and activation, which was essential for growth and survival of ER+ BC cells resistant to the ER antagonist. Therefore, therapeutically targeting HER3 with HER3-DXd, an antibody-drug conjugate (ADC) composed of a fully human anti-HER3 monoclonal antibody (patritumab) conjugated to a topoisomerase I inhibitor payload (an exatecan derivative) via a tetrapeptide-based cleavable linker, can be an effective treatment for tamoxifen-resistant (TMR) ER+ BC. After first assessing HER3-DXd as a single agent, we sought to identify a synergistic partner to maximize HER3-DXd’s antitumor activity in HER3+/ER+ TMR BC. Methods: Whole-genome high-throughput siRNA screening was performed to identify targets whose inhibition enhances HER3-DXd’s antitumor efficacy. The antitumor effects of HER3-DXd plus the synergistic partners were assessed using a soft agar colony formation assay and a clonogenic assay in TMR HER3+/ER+ MCF7 and T47D BC cells. Treatment effects on cell cycle distribution, apoptosis, and expression of proteins that regulate cell cycle progression were assessed by flow cytometry, annexin V-PE and 7-AAD staining, and Western blotting, respectively. Results: HER3-DXd inhibited the anchorage-independent growth of HER3+/ER+ cells by >50% at 5 nM and their colony formation at 5-25 nM (P<0.05). To maximize HER3-DXd’s antitumor efficacy, we performed high-throughput siRNA screening and identified ATR, CD247, RAB7A, UPK3A, ROCK2, SLC29A1, and WNT7A as potential synergistic targets. Among these targets, inhibiting ATR with siRNA or BAY1895344 showed the most synergistic effect with HER3-DXd in HER3+/ER+ BC cells. In contrast, no synergistic effect was observed with the combination of BAY1895344 plus patritumab or control ADC (IgG-DXd), suggesting its dependence on HER3-DXd-mediated delivery of DXd. The combination of HER3-DXd plus BAY1895344 reprogrammed cell cycle progression from G2/M arrest to G1 arrest by inhibiting both ATR/Chk1/cyclin A2/CDK2 and ATR/Chk1/cyclin E/CDK2 signaling. The combination also reduced expression of H2AX, an ATR substrate that contributes to DNA repair, but increased that of γH2AX, indicating the induction of DNA damage. HER3-DXd and BAY1895344 synergistically inhibited growth of HER3+/ER+ BC cells by inducing apoptosis. Conclusion: The combination of HER3-DXd plus ATR inhibitors has therapeutic potential for overcoming tamoxifen resistance in HER3+/ER+ BC. We are currently validating the synergy in endocrine-resistant ER+ BC xenograft models. Citation Format: Xuemei Xie, Jangsoon Lee, Jon A. Fuson, Huey Liu, Young Jin Gi, Pang-Dian Fan, Kumiko Koyama, Debu Tripathy, Naoto T. Ueno. Targeting ATR enhances the antitumor efficacy of patritumab deruxtecan (HER3-DXd) in tamoxifen-resistant ER+ breast cancer cells by reprogramming cell cycle progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB088.

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Beckford-Vera, Denis, Jason Li, Caroline Jennings, Megan McCloskey, Amanda Chin, Qing Liang, Jesse Hwang, Monideepa Roy, Mary Chen e Helen Kotanides. "Abstract 609: Anti-HER3 radioimmunotherapy enhances the anti-tumor effects of CD47 blockade in solid tumors". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 609. http://dx.doi.org/10.1158/1538-7445.am2022-609.

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Abstract Background: Cancer immunotherapy strategies targeting blockade of the CD47-SIRPα immunosuppressive signal have made significant progress in recent years. However, monotherapies have not shown meaningful clinical responses in solid tumors. Therefore, therapeutic combinations are being explored to improve patient outcomes. CD47 is a macrophage checkpoint inhibitor that acts as a “don’t eat me” signal on cancer cells to evade innate immune detection and destruction. Targeted radiation to cancer cells will upregulate calreticulin (CRT), a pro-phagocytic “eat me” signal. We therefore hypothesize that we can enhance the efficacy of anti-CD47 antibodies by combining them with appropriate targeted antibody radioconjugates (ARC). In this experiment we chose to study an anti-HER3 radioconjugate, as HER3 is overexpressed in a variety of cancers including breast, ovarian, lung, gastric and prostate and is associated with poor clinical prognosis. Additionally, upregulation of HER3 is implicated in the acquired resistance against HER1 or HER2 targeted therapies. Here, we demonstrate enhanced therapeutic efficacy of a novel Actinium-225 (225Ac) armed HER3 specific targeting ARC (225Ac-HER3-ARC) and a CD47 blocking antibody (anti-CD47) combination in preclinical solid tumor models. Methods: The anti-HER3 antibody (AT-02) was radiolabeled with 225Ac. 225Ac-HER3-ARC biological activity was evaluated using human recombinant HER3 and receptor positive tumor cell lines. 225Ac-HER3-ARC mediated CRT upregulation and cytotoxicity was evaluated using flow cytometry and MTS assay, respectively. The benefits of the 225Ac-HER3-ARC and anti-CD47 combination to enhance macrophage phagocytosis was evaluated by flow cytometry. We further evaluated the therapeutic benefits of the 225Ac-HER3-ARC and CD47 combination in human HER3+ tumor xenograft mouse model. Results: The 225Ac-HER3-ARC retains similar binding properties to native antibody and demonstrates specific cytotoxicity on tumor cells. CRT was upregulated by 225Ac-HER3-ARC in HER3+ cells. Furthermore, the combination of 225Ac-HER3-ARC and anti-CD47 enhances in vitro macrophage mediated tumor cell phagocytosis compared to each agent alone. Importantly, the in vivo 225Ac-HER3-ARC and CD47 antibody combination shows enhanced antitumor effect with reduced toxicity and improved survival benefit in a human preclinical solid tumor model compared to anti-CD47 agent alone. Conclusions: We demonstrate enhanced efficacy of the 225Ac-HER3-ARC and CD47 blocking antibody combination in vitro and in a preclinical solid tumor animal model. This approach is an encouraging strategy to potentially improve antitumor responses in patients with HER3+ tumors. Consequently, the findings obtained in this study along with the need to develop better therapies for patients with HER3+ tumors support the further preclinical development of HER3-ARC. Citation Format: Denis Beckford-Vera, Jason Li, Caroline Jennings, Megan McCloskey, Amanda Chin, Qing Liang, Jesse Hwang, Monideepa Roy, Mary Chen, Helen Kotanides. Anti-HER3 radioimmunotherapy enhances the anti-tumor effects of CD47 blockade in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 609.

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Chang, Chi-Son, Jung In Shim, Sun-Ju Byeon, Eun Jin Lee, Yoo-Young Lee, Tae-Joong Kim, Jeong-Won Lee, Byoung-Gie Kim e Chel Hun Choi. "Prognostic Significance of HER3 Expression in Patients with Cervical Cancer". Cancers 14, n. 9 (25 aprile 2022): 2139. http://dx.doi.org/10.3390/cancers14092139.

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HER3 has been recognized to have an oncogenic role in various types of cancer. However, its prognostic significance has not been elucidated in cervical cancer. The aim of this study was to investigate the prognostic significance of HER3 expression in cervical cancer using immunohistochemistry (IHC). HER3 immunohistochemical staining was performed on the tumor tissue samples of 336 cervical cancer patients. The association between the clinicopathological characteristics and patient survival analysis was assessed according to HER3 expression. HER3 IHC staining was positive in 31.0% (104/336) of the cervical cancer patients. A higher proportion of adeno-/adenosquamous carcinoma was observed in the HER3-positive group (34.6%) than in the HER3-negative group (18.8%). In survival analysis, HER3 expression was significantly associated with poorer disease-free survival (DFS) and overall survival (OS) (p < 0.001 and p = 0.002, respectively). Multivariate analysis also indicated that HER3 expression was an independent prognostic factor for DFS (hazard ratio (HR) = 2.58, 95% confidence interval (CI) 1.42–4.67, p = 0.002) and OS (HR = 3.21, 95% CI, 1.26–8.14, p = 0.014). HER3 protein expression was a poor prognostic factor of survival in patients with cervical cancer. This finding could help to provide individualized management for these patients.

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Chang, Chi-Son, Jung In Shim, Sun-Ju Byeon, Eun Jin Lee, Yoo-Young Lee, Tae-Joong Kim, Jeong-Won Lee, Byoung-Gie Kim e Chel Hun Choi. "Prognostic Significance of HER3 Expression in Patients with Cervical Cancer". Cancers 14, n. 9 (25 aprile 2022): 2139. http://dx.doi.org/10.3390/cancers14092139.

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HER3 has been recognized to have an oncogenic role in various types of cancer. However, its prognostic significance has not been elucidated in cervical cancer. The aim of this study was to investigate the prognostic significance of HER3 expression in cervical cancer using immunohistochemistry (IHC). HER3 immunohistochemical staining was performed on the tumor tissue samples of 336 cervical cancer patients. The association between the clinicopathological characteristics and patient survival analysis was assessed according to HER3 expression. HER3 IHC staining was positive in 31.0% (104/336) of the cervical cancer patients. A higher proportion of adeno-/adenosquamous carcinoma was observed in the HER3-positive group (34.6%) than in the HER3-negative group (18.8%). In survival analysis, HER3 expression was significantly associated with poorer disease-free survival (DFS) and overall survival (OS) (p < 0.001 and p = 0.002, respectively). Multivariate analysis also indicated that HER3 expression was an independent prognostic factor for DFS (hazard ratio (HR) = 2.58, 95% confidence interval (CI) 1.42–4.67, p = 0.002) and OS (HR = 3.21, 95% CI, 1.26–8.14, p = 0.014). HER3 protein expression was a poor prognostic factor of survival in patients with cervical cancer. This finding could help to provide individualized management for these patients.

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Amin, Dhara N., Natalia Sergina, Lionel Lim, Andrei Goga e Mark M. Moasser. "HER3 signalling is regulated through a multitude of redundant mechanisms in HER2-driven tumour cells". Biochemical Journal 447, n. 3 (5 ottobre 2012): 417–25. http://dx.doi.org/10.1042/bj20120724.

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HER2 (human epidermal growth factor receptor-2)-amplified tumours are characterized by constitutive signalling via the HER2–HER3 co-receptor complex. Although phosphorylation activity is driven entirely by the HER2 kinase, signal volume generated by the complex is under the control of HER3, and a large capacity to increase its signalling output accounts for the resiliency of the HER2–HER3 tumour driver and accounts for the limited efficacies of anti-cancer drugs designed to target it. In the present paper we describe deeper insights into the dynamic nature of HER3 signalling. Signalling output by HER3 is under several modes of regulation, including transcriptional, post-transcriptional, translational, post-translational and localizational control. These redundant mechanisms can each increase HER3 signalling output and are engaged in various degrees depending on how the HER3/PI3K (phosphoinositide 3-kinase)/Akt/mTOR (mammalian target of rapamycin) signalling network is disturbed. The highly dynamic nature of HER3 expression and signalling, and the plurality of downstream elements and redundant mechanisms that function to ensure HER3 signalling throughput identify HER3 as a major signalling hub in HER2-amplified cancers and a highly resourceful guardian of tumorigenic signalling in these tumours.

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Rajendran, Rithika, Coen Johannes Gerardus Lap, Fayez Estephan, Shanshan Liu, Ramesh Subrahmanyam, Guoqing Diao, Victor Nava e Maneesh Rajiv Jain. "Prevalence of HER3 expression in prostate adenocarcinoma and its clinicopathological characteristics." Journal of Clinical Oncology 42, n. 16_suppl (1 giugno 2024): 5019. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.5019.

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5019 Background: Human epidermal growth factor receptor 3 (HER3) has been found upregulated in a wide variety of cancers and has been associated with disease progression and resistance to EGFR-targeted therapies in HER2-positive malignancies. Several studies have reported expression of HER3 in prostate cancer (PCa). Furthermore, concurrent expression of HER2 and HER3 in PCa has been associated with androgen resistance, development of metastatic disease, and less favorable outcomes. However, due to conflicting results, the exact nature of the relationship between HER2 and HER3 in PCa requires further investigation. Methods: 194 patients diagnosed with PCa between 2000-2021 at the Washington DC Veterans Affairs Medical Center who had adequate formalin-fixed paraffin embedded prostate tissue available were selected from our previously published cohort of patients. HER3 immunostaining was performed and independently scored by two pathologists as 0 (absent), 1+ (weak), 2+ (moderate), or 3+ (marked). HER2 immunostaining data and clinical information was retrieved. Statistical analysis included Fisher’s exact test and linear regression models. Results: In our self-identified predominantly African American (85%) patient cohort, a 94% overall prevalence of HER3 positivity (1+, 2+, or 3+) was observed. Notably, the majority of positive patients was found to have HER3 expression of either 2+ (~60%; 116/194) or 3+ (~17%; 33/194). HER3 positivity was associated with a higher PSA ( p=0.023), a higher Grade Group (GG) ( p=0.017), and a higher AJCC disease stage ( p=0.006) at time of diagnosis (Table 1). A significant association was observed between positivity for both HER2 and HER3 ( p=0.031). HER3 positivity independently predicted GG ( p=0.02) and AJCC disease stage ( p=0.01) when adjusted for HER2 positivity. Conclusions: In this predominantly African American cohort, a high prevalence of HER3 positivity was observed across PCa disease stages. Higher expression levels of HER3 were observed in more advanced stages of the disease. Because of the observed efficacy of HER3-antibody drug conjugates in other HER3-expressing malignancies, the high prevalence of HER3 in PCa makes it an attractive therapeutic target that warrants further evaluation.[Table: see text]

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Yonesaka, Kimio, Junko Tanizaki, Osamu Maenishi, Koji Haratani, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi et al. "Dynamics of HER3 and its correlated gene expression profile in EGFR-mutated NSCLC tumor treated with EGFR-TKI toward enhancing effectiveness of patritumab deruxtecan (HER3-DXd; U3-1402)." Journal of Clinical Oncology 40, n. 16_suppl (1 giugno 2022): e21175-e21175. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21175.

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e21175 Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for activated EGFR-mutated non-small-cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance and is hence a promising target for anticancer treatment. Patritumab deruxtecan (HER3-DXd) is an antibody drug conjugate comprised of a fully human anti-HER3 IgG1 monoclonal antibody, covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker. Clinical trials of theHER3-DXd demonstrated its anticancer activity in EGFR-mutated NSCLC. However, the genomic background that regulates HER3 expression is unknown. This study was conducted with the aim to clarify the genomic background for HER3 regulation in EGFR-mutated NSCLC tumors and to explore the strategy for enhancing the anticancer activity of HER3-DXd. Methods: 48 paired samples were obtained before EGFR-TKI treatment and after the acquisition of EGFR-TKI resistance from patients with EGFR-mutated NSCLC. HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pre-treatment to post-EGFR-TKI resistance acquisition. For statistical tests, linear regression analysis was performed to investigate whether a factor, including EGFR-TKI administration, affected HER3 expression. Pearson correlation coefficients were calculated to explore the relationships between HER3 expression level and other genomic expression in the tumors. Results: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared to paired pretreatment samples (mean H-score 100.8 vs. 155.9, paired t-test p = 0.0007). Although genomic alterations including EGFR secondary T790M mutation did not correlate with HER3 augmentation, RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation (GSEA; normalized enrichment score -1.78, p = 0.004). Multivariable regression analysis of HER3 augmentation revealed that re-biopsy under continuing EGFR-TKI treatment independently effected HER3 augmentation. Indeed, an in-vitro study also showed that EGFR-TKI increased HER3 expression via repressed AKT phosphorylation in multiple EGFR-mutated cancers, and it finally enhanced the anticancer activity of HER3-DXd. Conclusions: Our findings highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC that is currently being evaluated in a clinical trial for patients with EGFR-mutated NSCLC tumors, not only with regard to an acquired resistance to EGFR-TKI but also in EGFR-TKI-naïve tumors (NCT04676477).

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Yonesaka, Kimio, Junko Tanizaki, Osamu Maenishi, Koji Haratani, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi et al. "Dynamics of HER3 and its correlated gene expression profile in EGFR-mutated NSCLC tumor treated with EGFR-TKI toward enhancing effectiveness of patritumab deruxtecan (HER3-DXd; U3-1402)." Journal of Clinical Oncology 40, n. 16_suppl (1 giugno 2022): e21175-e21175. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21175.

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e21175 Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for activated EGFR-mutated non-small-cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance and is hence a promising target for anticancer treatment. Patritumab deruxtecan (HER3-DXd) is an antibody drug conjugate comprised of a fully human anti-HER3 IgG1 monoclonal antibody, covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker. Clinical trials of theHER3-DXd demonstrated its anticancer activity in EGFR-mutated NSCLC. However, the genomic background that regulates HER3 expression is unknown. This study was conducted with the aim to clarify the genomic background for HER3 regulation in EGFR-mutated NSCLC tumors and to explore the strategy for enhancing the anticancer activity of HER3-DXd. Methods: 48 paired samples were obtained before EGFR-TKI treatment and after the acquisition of EGFR-TKI resistance from patients with EGFR-mutated NSCLC. HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pre-treatment to post-EGFR-TKI resistance acquisition. For statistical tests, linear regression analysis was performed to investigate whether a factor, including EGFR-TKI administration, affected HER3 expression. Pearson correlation coefficients were calculated to explore the relationships between HER3 expression level and other genomic expression in the tumors. Results: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared to paired pretreatment samples (mean H-score 100.8 vs. 155.9, paired t-test p = 0.0007). Although genomic alterations including EGFR secondary T790M mutation did not correlate with HER3 augmentation, RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation (GSEA; normalized enrichment score -1.78, p = 0.004). Multivariable regression analysis of HER3 augmentation revealed that re-biopsy under continuing EGFR-TKI treatment independently effected HER3 augmentation. Indeed, an in-vitro study also showed that EGFR-TKI increased HER3 expression via repressed AKT phosphorylation in multiple EGFR-mutated cancers, and it finally enhanced the anticancer activity of HER3-DXd. Conclusions: Our findings highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC that is currently being evaluated in a clinical trial for patients with EGFR-mutated NSCLC tumors, not only with regard to an acquired resistance to EGFR-TKI but also in EGFR-TKI-naïve tumors (NCT04676477).

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Kim, Joori, Jeong-Oh Kim, Youn Soo Lee, Jung-Young Shin, Min Young Kim, Mi-Ran Lee, Seoree Kim et al. "The changes of HER3 expression in head and neck cancer patients treated with induction chemotherapy." Journal of Clinical Oncology 41, n. 16_suppl (1 giugno 2023): e18004-e18004. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e18004.

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e18004 Background: Erb-b2 receptor tyrosine kinase 3 (HER3) is broadly expressed in various types of cancer and is associated with poor prognosis. Recent evidence supports HER3 plays a role in acquired resistance to chemotherapy. The change of HER3 expression by chemotherapy in head and neck squamous cell carcinoma (HNSCC) remains unclear. Methods: We evaluated 95 patients with locally advanced HNSCC who had received induction chemotherapy (ICT) between 2009 and 2019. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. H-score of membrane staining was evaluated. Results: Median age of patients was 64 years, and 85% were male. Primary locations included oropharynx (54.8%), hypopharynx (21.5%), oral cavity (17.2%), and salivary gland (6.5%). Mean H-score of HER3 in tumor tissues was 77.6 ± 7.9. H-score of HER3 in HPV-positive tumors was higher than HPV-negative tumors (p = 0.019), which was more pronounced in oropharynx and hypopharynx tumors. While, H-score of HER3 in adjacent normal tissues of these tumors did not significantly differ. Compared with the non-smokers, tumor tissues of current or ex-smokers demonstrated higher H-score of HER3 (p = 0.033), independent of tumor location. In contrast, in adjacent normal tissues, no significant differences of H-score of HER3 were observed depending on the smoking status. The H-score higher than 100 was defined as HER3-high group. Among oropharynx and hypopharynx tumors with positive correlation between H-score of HER3 and HPV status (n = 56), HER3-high group was significantly correlated with HPV positivity (p = 0.009) and good response to ICT (p = 0.035). Good clinical response was also strongly related to HPV-positivity (p = 0.001). In addition, there was a tendency for longer overall survival in HER3-high group than low HER3 expression group (93 vs. 70 months, p = 0.053). The paired tumor samples collected at pre- and post-ICT (n = 21) were analyzed. HER3 expressions in adjacent normal tissue were higher at post-ICT compared to pre-ICT (p = 0.003), and these results were more pronounced in the non-smoking group, but no differences were found according to HPV-status. Conclusions: Taken together, our results showed that H-score of HER3 was significantly higher in both HPV-positive and smoking group. Interestingly, high HER3 expression in oropharynx and hypopharynx tumors was associated with HPV positivity and good clinical response to ICT. Additional analysis of tumor immune microenvironment in tumor tissues are underway.

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Mishra, Rosalin, Mary Kate Kilroy, Wasim Feroz, Hima Patel, Samar Alanazi e Joan T. Garrett. "Abstract 3916: role of her3 v104l mutation on tumor growth and her3 stabilization". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 3916. http://dx.doi.org/10.1158/1538-7445.am2023-3916.

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Abstract We aimed to determine if naturally occurring HER3 mutations could drive oncogenic activity of HER2+ HCC1569 cells in which endogenous HER3 was knocked out using CRISPR-Cas9 technology. A series of HER3 mutations found in breast cancer patients (F94L, V104L, G284R, D297Y, T355I, and E928G) were introduced via lentiviral transduction and stable cell lines were generated in HER3 knock out (KO) HCC1569 cells and were maintained in 0.5 mg/mL puromycin. Our data indicated that cells stably transduced with HER3V104L mutation had significantly higher cell growth with higher p-HER3 expression versus wild-type (wt) and empty-vector (EV) HER3. We found that HCC1569HER3KO cells with WT and V104L were sensitive to increasing concentration of neratinib (0.1-0.5 µM) as indicated by crystal violet assay. Next we examined if V104L mutation rendered resistance to another FDA- approved irreversible HER2 tyrosine kinase inhibitor, tucatinib. Our results showed that V104L cells were sensitive to higher concentration of tucatinib compared to neratinib. In other experiments, we used COS7 cells to examine the signaling pathways of HER3V104L mutation. Our western blot data demonstrated that transient transfection of COS7 cells with HER3V104L mutant significantly upregulated p-HER3 and p-HER2 expression versus WT HER3 in a NRG- dependent manner. In addition, we found that the V104L mutation stabilizes HER3 protein expression independent of ligand stimulation. Our western blot data showed that V104L induced HER3 stabilization is independent on HER3 binding partners HER1, HER2 and HER4. Our cycloheximide chase data indicated that V104L mutation stabilizes HER3 expression in COS7 cells as well as low HER3 expressing colon cancer cell line, SNUC5. Our western blot data indicates that V104L mutation activates ERK signaling in NRG dependent manner over AKT pathway in COS7 cells. In addition, we are using various PDXs with different HER3 mutations (V104M and E928D) to determine the role of these driver HER3 mutations in cancer and how this can be targeted in the clinic using HER targeted therapy. Citation Format: Rosalin Mishra, Mary Kate Kilroy, Wasim Feroz, Hima Patel, Samar Alanazi, Joan T. Garrett. role of her3 v104l mutation on tumor growth and her3 stabilization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3916.

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Òdena, Andreu, Laia Monserrat, Fara Brasó-Maristany, Marta Guzmán, Judit Grueso, Olga Rodríguez, Maurizio Scaltriti et al. "Abstract P5-13-14: Antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3-directed antibody drug conjugate (ADC) across a diverse panel of breast cancer (BC) patient-derived xenografts (PDXs)". Cancer Research 82, n. 4_Supplement (15 febbraio 2022): P5–13–14—P5–13–14. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-13-14.

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Abstract Background: HER3 is overexpressed in 30-50% of breast cancers and has been associated with poor prognosis. Patritumab deruxtecan (HER3-DXd; U3-1402) is a HER3-directed ADC with a potent topoisomerase I (TOP1) inhibitor payload. A phase 1/2 study of HER3-DXd (NCT02980341) demonstrated promising antitumor activity in hormone receptor positive (HR+) metastatic BC patients with clinical activity observed across baseline levels of HER3 protein or mRNA expression. A window of opportunity clinical trial is currently ongoing to evaluate the biological activity of HER3-DXd in patients with treatment naïve BC according to HER3 mRNA/protein expression levels (NCT04610528). Here, we aimed to describe the activity of HER3-DXd in PDX models to identify robust biomarkers of response. Methods: The antitumor activity of HER3-DXd was assessed in 21 BC PDX models (14 HR+ and 7 triple negative). HER3-DXd sensitivity was established as a complete response that lasted longer than 120 days, following 4 weekly doses of 10 mg/kg. HER3-DXd antitumor activity was compared to the antitumor activity of irinotecan (50 mg/kg dosed once weekly), which was evaluated according to modified RECIST criteria in a subset of 14 BC PDX models. PDX models of acquired resistance to HER3-DXd were generated by repeated treatment cycles. Pharmacodynamic (PD) experiments were conducted by collecting tumor samples from PDXs after a single dose of HER3-DXd or irinotecan. Baseline HER3 expression was assessed by immunohistochemistry (IHC) and Western blot. mRNA expression of 72 genes including ERBB3 and genes from the PAM50 signature were measured using the nCounter platform. Two-class unpaired significance analysis of microarrays (SAM), using a false-discovery rate<5%, identified differential gene expression across response groups. Genetic alterations harbored by PDX models were determined using the MSK-IMPACTTM targeted exome panel. Quantification of proliferation (% of Ki67-positive cells) and of DNA damage during the S-phase of the cell cycle (γH2AX nuclear foci in geminin-positive cells) was evaluated in untreated/treated PD samples by IHC or immunofluorescence (IF), respectively. Western blot was used to assess HER3-pathway downmodulation and induction of apoptosis. Results: Eight out of 21 (38%) PDXs were highly sensitive to HER3-DXd, and in 5/14 (36%) models HER3-DXd showed a superior antitumor activity when compared to irinotecan. We observed an enrichment of basal-like models amongst the non-relapsed PDXs, compared to the relapsed ones (6/8 (75%) vs. 3/13 (20%), p=0.0195). Baseline levels of HER3/ERBB3 were not associated with treatment response and a model of acquired-resistance did not exhibit a reduction in baseline HER3 expression. Interestingly, relapsed models showed increased expression of genes related with chemotherapy-resistance (MDM2, NAT1, MAPT, GRB7, BCL-2). Mechanistically, treatment with HER3-DXd did not reduce the level of Ki67-proliferating cells but resulted in a significantly higher induction of S-phase DNA damage measured as γH2AX nuclear foci in non-relapsed models, compared to relapsed ones. This was accompanied by a reduction of HER3 protein levels and downmodulation of pERK1/2 T202/Y204, along with activation of PARP cleavage. Conclusions: HER3-DXd exerts a potent antitumor response in BC PDXs, independently of baseline HER3/ERBB3 levels, in line with the clinical data of NCT02980341. Basal-like tumors were more sensitive to HER3-DXd than luminal B models. Mechanistically, our data suggests that treatment with HER3-DXd results in parallel HER3/ERK signaling downmodulation and induction of S-phase DNA damage, resulting in tumor cell death. Citation Format: Andreu Òdena, Laia Monserrat, Fara Brasó-Maristany, Marta Guzmán, Judit Grueso, Olga Rodríguez, Maurizio Scaltriti, Sarat Chandarlapaty, Yang Qiu, Kumiko Koyama, Mafalda Oliveira, Aleix Prat, Violeta Serra. Antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3-directed antibody drug conjugate (ADC) across a diverse panel of breast cancer (BC) patient-derived xenografts (PDXs) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-14.

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Manickavasagar, Thubeena, Wei Yuan, Suzanne Carreira, Bora Gurel, Susana Miranda, Ana Ferreira, Mateus Crespo et al. "HER3 expression and MEK activation in non-small-cell lung carcinoma". Lung Cancer Management 10, n. 2 (giugno 2021): LMT48. http://dx.doi.org/10.2217/lmt-2020-0031.

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Aim: We explore HER3 expression in lung adenocarcinoma (adeno-NSCLC) and identify potential mechanisms of HER3 expression. Materials & methods: Tumor samples from 45 patients with adeno-NSCLC were analyzed. HER3 and HER2 expression were identified using immunohistochemistry and bioinformatic interrogation of The Cancer Genome Atlas (TCGA). Results: HER3 was highly expressed in 42.2% of cases. ERBB3 copy number did not account for HER3 overexpression. Bioinformatic analysis of TCGA demonstrated that MEK activity score (a surrogate of functional signaling) did not correlate with HER3 ligands. ERBB3 RNA expression levels were significantly correlated with MEK activity after adjusting for EGFR expression. Conclusion: HER3 expression is common and is a potential therapeutic target by virtue of frequent overexpression and functional downstream signaling.

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Rathore, Moeez Ghani, Wei Zhang, Michel'le Wright, Jordan Winter, Yamu Li, Zhenghe Wang e Rui Wang. "Abstract 3177: Liver endothelium secreted LRG1 is a novel ligand of HER3 to promote metastatic colorectal cancer growth". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 3177. http://dx.doi.org/10.1158/1538-7445.am2022-3177.

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Abstract Background: Liver is the most common site of developing distant metastasis in colorectal cancer (CRC). Patients with metastatic CRC (mCRC) have a 5-year survival rate at 14%. We previously showed that liver endothelial cells (EC), a key component of the liver microenvironment, secrete soluble factors to promote CRC growth and chemoresistance via activating human epidermal growth factor receptor (ERBB3, also known as HER3). However, we found that the ECs activated HER3 by a previously unknown mechanism that is independent of the established HER3 ligand neuregulins. Identifying a new HER3 ligand will potentially give rise to novel therapeutic target for treating patients with mCRC. Methods: We first fractionated conditioned medium (CM) from liver ECs by fast protein liquid chromatography. The specific fractions that activated HER3 and AKT in CRC cells were subjected to mass spectrometry (MS) for protein identification. In parallel, we used a His-tagged HER3 Extracellular domain (ECD) and pulled down EC-secreted factors that directly bound to HER3 and then subjected to protein identification by MS. Candidate proteins identified in both MS analyses were subjected for further validations by siRNA or immunoprecipitation depletion from EC CM to determine their roles in HER3 activation and CRC growth. Results: We identified a specific fraction of liver EC CM increased phosphorylation of HER3 and AKT in CRC cells (determined by Western blotting). Meanwhile, the HER3-ECD affinity binding assay showed that HER3 ECD-depleted EC CM could no longer activate HER3 or promote growth, and the soluble factor(s) eluted from HER3-ECD increased phosphorylation of HER3 and AKT, and promoted growth in CRC cells. Results from both MS analyses revealed that LRG1 is a potential ligand that binds to and activate HER3 in CRC cells. We depleted LRG1 from EC CM, either by siRNA knockdown LRG1 in ECs or immunoprecipitation, and found that LRG1-depleted EC CM could no longer activate HER3 and AKT in CRC cells, and LRG1-depleted EC CM failed to promote growth of CRC cell in vitro and CRC xenografts in vivo. Conclusions: We identified LRG1 as a new HER3 ligand and demonstrated that liver EC-secreted LRG1 mediates EC paracrine effects on activating HER3 and promoting CRC cell growth. Our findings suggest an oncogenic role of EC-secreted LRG1 in the surrounding liver microenvironment of mCRC, and highlighted a potential of blocking LRG1 with monoclonal antibodies for treating patients with mCRC. Citation Format: Moeez Ghani Rathore, Wei Zhang, Michel'le Wright, Jordan Winter, Yamu Li, Zhenghe Wang, Rui Wang. Liver endothelium secreted LRG1 is a novel ligand of HER3 to promote metastatic colorectal cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3177.

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Nishioka, Mariko, Chigusa Morizane, Mao Okada, Tomoyuki Satake, Nobuyoshi Hiraoka, Satoshi Nara, Tomoya Kakegawa et al. "HER3 expression status following systemic chemotherapy treatment in biliary tract cancers." Journal of Clinical Oncology 41, n. 16_suppl (1 giugno 2023): e16153-e16153. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e16153.

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e16153 Background: Erb-b2 receptor tyrosine kinase 3 (HER3) is frequently overexpressed in a variety of cancers. Activation of HER3 signaling serves an important role in promoting cell proliferation and is associated with chemoresistance. Thus, there is interest in exploring HER3 status of tumors as a potential prognostic and/or therapeutic target. Prior studies have reported HER3 status in various cancers after treatment with chemotherapy (CT). However, HER3 expression profile in biliary tract cancer (BTC) remains unknown. Here, we evaluated HER3 status of patients with BTC post CT. Methods: The medical records of patients (pts) who had been initially diagnosed with BTC and treated at the National Cancer Center Hospital (Tokyo, Japan), between January 2010 and June 2020, were retrospectively analyzed. Pts whose post CT specimens were available were included in this study. Immunohistochemical staining for HER3 was performed using HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology) as a primary antibody. IHC scoring (0, 1+, 2+, 3+) of membranous staining intensity was performed according to HER2 IHC gastric scoring guideline. Results: A total of 19 pts with BTC, with a median age of 59 (range 44-79) years, had specimens available after post CT and were evaluated for HER3 expression status. HER3 status was 3+ in 10 pts, 2+ in 3 pts, 1+ in 4 pts, and 0 in 2 pts. The specimens were obtained from liver in 17 pts, bone in 1 pt, and omental lymph node in 1 pt. The histological type was adenocarcinoma in all pts, and HER3 status according to primary tumor type is shown in the table below. Fourteen pts were treated with gemcitabine (GEM) plus cisplatin (CDDP), 1 pt with GEM plus CDDP plus S-1, 1 pt with GEM plus S-1 as first-line CT for advanced BTC, and 3 pts with S-1 as an adjuvant treatment. Fifteen pts were biopsied after CT to participate in clinical trial. The remaining 4 obtained specimens after CT during primary surgery or surgery for metastases or for cholangitis. The median overall survival of pts with advanced BTC was 23.6 months in HER3 3+, 17.1 months in HER3 2+, 27.7 months in HER3 1+, and 24.6 months in HER3 0. Four pts had specimens available from pre and post CT, all of which were intrahepatic cholangiocarcinoma with the treatment of GEM plus CDDP. HER3 status was upregulated in 3 pts (1 pt 1+ to 2+, 2 pts 2+ to 3+) and downregulated in 1 pt (1+ to 0) at post CT. Conclusions: HER3 expression (1+, 2+, 3+) was observed in 89.5% of previously treated pts with BTC, and HER3 status was upregulated after CT in some pts. These results suggest that HER3 might be a potential therapeutic target in BTC post CT. [Table: see text]

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Xie, Xuemei, Jangsoon Lee, Jon A. Fuson, Huey Liu, Young J. Gi, Thanasis Poullikkas, Pang-Dian Fan, Kumiko Koyama, Debu Tripathy e Naoto T. Ueno. "Abstract LB042: Targeting ATR enhances the antitumor efficacy of patritumab deruxtecan (HER3-DXd)in tamoxifen-resistant ER+ breast cancer cells by inducing DNA damage and apoptosis". Cancer Research 83, n. 8_Supplement (14 aprile 2023): LB042. http://dx.doi.org/10.1158/1538-7445.am2023-lb042.

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Abstract Background: HER3, a member of the ERBB family of receptor tyrosine kinases that activates multiple oncogenic signaling pathways, is overexpressed in 50-70% of breast cancers (BC). HER3 mRNA expression is highest in luminal (ER+) breast tumors. Approximately 30% of ER+ breast tumors are de novo resistant to tamoxifen. Therefore, therapeutically targeting HER3 with HER3-DXd, an antibody-drug conjugate (ADC) composed of a fully human anti-HER3 IgG1 monoclonal antibody (patritumab) covalently linked to a topoisomerase I (TOP I) inhibitor payload (deruxtecan) via a tetrapeptide-based cleavable linker, can be an effective treatment for tamoxifen-resistant (TMR) ER+ BC. After assessing HER3-DXd’s efficacy as a single agent, we sought to identify a synergistic partner to maximize its antitumor activity in HER3+/ER+ TMR BC. Methods: Whole-genome high-throughput siRNA screening (Ambion Silencer Select Human Genome siRNA Library V4) was performed to identify synergistic partners for maximizing HER3-DXd’s antitumor efficacy. The synergistic antitumor effects were assessed in vitro using a soft agar colony formation assay and a clonogenic assay in TMR HER3+/ER+ MCF7 and T47D BC cells and in vivo using xenograft mouse models of these cells. Targeting specificity was determined using siRNA. Treatment effects on cell cycle progression, DNA damage, apoptosis, and expression of proteins of interest were assessed by flow cytometry, comet assay, staining with annexin V-PE and 7-AAD, and Western blotting, respectively. Results: HER3-DXd inhibited the anchorage-independent growth of HER3+/ER+ cells by >50% at 5 nM and their colony formation at 5-25 nM (P < 0.05). Among the synergistic targets identified by whole-genome high-throughput siRNA screening, inhibiting ATR with siRNA or BAY1895344 showed the greatest synergistic effect with HER3-DXd in TMR HER3+/ER+ BC cells. In contrast, no synergistic effect was observed with the combination of BAY1895344 plus patritumab or control ADC (IgG-DXd), suggesting its dependence on HER3-DXd-mediated delivery of DXd. To further confirm the targeting specificity, we knocked down ATR or TOP I expression using siRNA in TMR HER3+/ER+ BC cells and then treated the cells with HER3-DXd or BAY1895344, respectively. A synergy was also observed, indicating that the drugs achieve the synergy by targeting ATR and TOP I. The combination of HER3-DXd plus BAY1895344 reprogrammed cell cycle progression from G2/M arrest to sub-G1 arrest by inhibiting both ATR/Chk1/cyclin A2/CDK2 and ATR/Chk1/cyclin E/CDK2 signaling. The combination also induced DNA damage, which was further confirmed by the reduced expression of H2AX, an ATR substrate that contributes to DNA repair, and the increased expression of γH2AX (phospho-H2AX at Ser139), an indicator of DNA damage. HER3-DXd and BAY1895344 synergistically inhibited the growth of both TMR HER3+/ER+ MCF7 (P < 0.0001) and T47D (P < 0.01) xenografts in mice. Conclusion: The combination of HER3-DXd plus ATR inhibitors has therapeutic potential for overcoming tamoxifen resistance in HER3+/ER+ BC. Citation Format: Xuemei Xie, Jangsoon Lee, Jon A. Fuson, Huey Liu, Young J. Gi, Thanasis Poullikkas, Pang-Dian Fan, Kumiko Koyama, Debu Tripathy, Naoto T. Ueno. Targeting ATR enhances the antitumor efficacy of patritumab deruxtecan (HER3-DXd)in tamoxifen-resistant ER+ breast cancer cells by inducing DNA damage and apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB042.

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Kilroy, Mary Kate, SoYoung Park, Wasim Feroz, Hima Patel, Rosalin Mishra, Samar Alanazi e Joan T. Garrett. "HER3 Alterations in Cancer and Potential Clinical Implications". Cancers 14, n. 24 (14 dicembre 2022): 6174. http://dx.doi.org/10.3390/cancers14246174.

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In recent years, the third member of the HER family, kinase impaired HER3, has become a target of interest in cancer as there is accumulating evidence that HER3 plays a role in tumor growth and progression. This review focuses on HER3 activation in bladder, breast, colorectal, and lung cancer disease progression. HER3 mutations occur at a rate up to ~10% of tumors dependent on the tumor type. With patient tumors routinely sequenced for gene alterations in recent years, we have focused on HER3 mutations in bladder, breast, colon, and lung cancers particularly in response to targeted therapies and the potential to become a resistance mechanism. There are currently several HER3 targeting drugs in the pipeline, possibly improving outcomes for cancer patients with tumors containing HER3 activation and/or alterations.

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Mishra, Rosalin, Mary Kate Kilroy, Hima Patel, Samar Alanazi e Joan T. Garrett. "Abstract 5412: Role of her3 mutations on breast cancer oncogenesis". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 5412. http://dx.doi.org/10.1158/1538-7445.am2022-5412.

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Abstract We sought to determine if naturally occurring mutations in HER3 could drive oncogenic growth of HER3KO HER2+ HCC1569 cells in which endogenous HER3 has been eliminated via CRISPR-Cas9. A series of HER3 mutations identified in breast cancer patients (F94L, V104L, G284R, D297Y, T355I, and E928G) were introduced using lentiviral transduction and stable cell lines were generated in HER3KOHCC1569 cells via puromycin selection. We identified HER3V104L mutation to have higher cell proliferation and higher p-HER3 expression compared to wild-type (wt) and empty-vector (EV) HER3. We observed that HCC1569HER3KO cells stably expressing WT and V104L were sensitive to increasing doses of neratinib (0.1-0.5 µM) concentration. Next we analyzed if this mutation rendered resistance to the recently FDA- approved irreversible HER2 tyrosine kinase inhibitor, tucatinib. Our data indicated that both that V104L cells were sensitive to higher concentration of tucatinib compared to neratinib. In parallel experiments, we utilized COS7 cells to examine the signaling properties of HER3V104L. Our data indicated that transient transfection of COS7 cells with HER3V104L mutant significantly induces p-HER3/p-AKT and p-HER2 expression compared to WT HER3 in a ligand dependent manner. In addition, we observed that the V104L mutation stabilizes HER3 protein expression independent of HER2 and ligand stimulation. Experiments are ongoing to determine whether V104L induced HER3 stabilization and downstream signaling activation is dependent on HER3 binding partners including EGFR, HER2 or HER4. We also aim to understand how the V104L mutation stabilizes HER3 expression. Structural modeling of V104L mutation will provide insight about the mechanism of stabilization of the HER3 protein. We will use MCF10A and HEK293 cells to determine the effect of the V104L mutation on HER3 expression and downstream signaling. We also aim to decipher the signaling mechanism that drives the oncogenic potential of V104L mutation. In addition, we are using various PDXs with different HER3 mutations to determine other driver HER3 mutations in breast cancer and how this can be targeted in the clinic using HER targeted therapy. Citation Format: Rosalin Mishra, Mary Kate Kilroy, Hima Patel, Samar Alanazi, Joan T. Garrett. Role of her3 mutations on breast cancer oncogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5412.

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Hwang, Hae Min, So Hyeon Kim, Sujin Ham, Minyoung Lee, Youlim Noh, Yu-Jin Kim, Changyun Lee et al. "Abstract C120: Antitumor effect of HER3-DXd, an antibody-drug conjugate targeting HER3, in gastric cancer cell lines". Molecular Cancer Therapeutics 22, n. 12_Supplement (1 dicembre 2023): C120. http://dx.doi.org/10.1158/1535-7163.targ-23-c120.

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Abstract Background: HER3, one of the HER family members, is expressed across various solid tumors and known to be an important oncogenic driver. HER3-DXd is an antibody-drug conjugate (ADC) that combines patritumab, an anti-HER3 antibody, and deruxtecan, a topoisomerase 1 inhibitor payload through peptide cleavable linker system. HER3-DXd has been shown to have anti-tumor effects in breast, non-small cell lung, and colorectal cancers, in vitro and in vivo, and is being evaluated in phase 2 and phase 3 clinical trials. However, the effect of HER3-DXd in gastric cancer and the mechanism of sensitivity are largely unknown. Methods: Seven gastric cancer cell lines were used (NUGC-4, NCI-N87, SNU-601, SNU-216, SNU-638, SNU-668, and MKN-45). Colony formation assay (CFA) was performed with increasing concentration of HER3-DXd (doses range: 0-100 nM) for 14 days. Cell cycle change and internalization of HER3-DXd bound to HER3 protein in the cell membrane were seen by flow cytometry analysis. Apoptotic cell death was assessed by Annexin-V assay. DNA strand breaks were examined using alkaline comet assay. DNA damage accumulation and TOP1-cleavage complexes (TOP1ccs) were identified using immunofluorescence assay. Results: Seven gastric cancer cell lines showed heterogeneous mRNA expression of HER2 and HER3, which correlated with protein expression. Three cell lines with different sensitivities to HER3-DXd were selected based on CFA. SNU-601 was sensitive to U3-1402 (IC50 value: 11.01 nM), SNU-638 was less sensitive (IC50 value: 50.04 nM), and SNU-668 was insensitive (IC50 value >100 nM). HER3-DXd increased the Annexin-V positive population and the sub-G1 population in SNU-601 and SNU-638 cells. Moreover, cleavage of PARP and caspase-3 were increased in SNU-601 and SNU-638 cells, but not in SNU-668 cells. HER3-DXd was efficiently internalized within 1 hour in all three cells, regardless of their sensitivities to HER3-DXd. Signal transduction through the HER2 and HER3 receptors, which mediates a PI3K-AKT signaling pathway, was inhibited in SNU-601 cells. In SNU-601 and SNU-638 cells, HER3-DXd increased the expression of γ-H2AX and length of the comet tails, which indicate DNA damage. HER3-DXd also induced topoisomerase 1 cleavage complexes (TOP1ccs) in SNU-601 and SNU-638 cells. In contrast, TOP1cc was not observed in resistant SNU-668 cells. Conclusion: HER3-DXd induced formation of TOP1ccs, subsequent DNA damage, and apoptotic cell death in sensitive cell lines, but not in an insensitive cell line. These data indicate that internalized HER3-DXd causes accumulation of DNA damage through TOP1cc formation, which leads to apoptotic cell death in gastric cancer. Citation Format: Hae Min Hwang, So Hyeon Kim, Sujin Ham, Minyoung Lee, Youlim Noh, Yu-Jin Kim, Changyun Lee, Jinyoung Kim, Dae-Won Lee, Kyung-Hun Lee, Seock-Ah Im. Antitumor effect of HER3-DXd, an antibody-drug conjugate targeting HER3, in gastric cancer cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C120.

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Hong, Woojae, Jeon Hwang-Bo, Hyelin Jeon, Minsung Ko, Joongyeon Choi, Yong-Joon Jeong, Jae-Hyun Park et al. "A Comparative Study of the Hepatoprotective Effect of Centella asiatica Extract (CA-HE50) on Lipopolysaccharide/d-galactosamine-Induced Acute Liver Injury in C57BL/6 Mice". Nutrients 13, n. 11 (15 novembre 2021): 4090. http://dx.doi.org/10.3390/nu13114090.

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Acute liver failure (ALF) refers to the sudden loss of liver function and is accompanied by several complications. In a previous study, we revealed the protective effect of Centella asiatica 50% ethanol extract (CA-HE50) on acetaminophen-induced liver injury. In the present study, we investigate the hepatoprotective effect of CA-HE50 in a lipopolysaccharide/galactosamine (LPS-D-Gal)-induced ALF animal model and compare it to existing therapeutic silymarin, Lentinus edodes mycelia (LEM) extracts, ursodeoxycholic acid (UDCA) and dimethyl diphenyl bicarboxylate (DDB). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were decreased in the CA-HE50, silymarin, LEM, UDCA and DDB groups compared to the vehicle control group. In particular, AST and ALT levels of the 200 mg/kg CA-HE50 group were significantly decreased compared to positive control groups. Lactate dehydrogenase (LDH) levels were significantly decreased in the CA-HE50, silymarin, LEM, UDCA and DDB groups compared to the vehicle control group and LDH levels of the 200 mg/kg CA-HE50 group were similar to those of the positive control groups. Superoxide dismutase (SOD) activity was significantly increased in the 100 mg/kg CA-HE50, LEM and UDCA groups compared to the vehicle control group and, in particular, the 100 mg/kg CA-HE50 group increased significantly compared to positive control groups. In addition, the histopathological lesion score was significantly decreased in the CA-HE50 and positive control groups compared with the vehicle control group and the histopathological lesion score of the 200 mg/kg CA-HE50 group was similar to that of the positive control groups. These results show that CA-HE50 has antioxidant and hepatoprotective effects at a level similar to that of silymarin, LEM, UDCA and DDB, which are known to have hepatoprotective effects; further, CA-HE50 has potential as a prophylactic and therapeutic agent in ALF.

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Tanner, Berno, Dirk Hasenclever, Katja Stern, Wiebke Schormann, Martin Bezler, Matthias Hermes, Marc Brulport et al. "ErbB-3 Predicts Survival in Ovarian Cancer". Journal of Clinical Oncology 24, n. 26 (10 settembre 2006): 4317–23. http://dx.doi.org/10.1200/jco.2005.04.8397.

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Background HER3 (erbB-3) is a member of the epidermal growth factor receptor (EGFR) family. After dimerization with other members of the EGFR family several signal transduction cascades can be activated, including phosphoinosite 3′-kinase (PI3-K)/Akt and extracellular signal-regulated kinase (ERK1/2). Here, we studied a possible association between HER3 expression and prognosis in patients with ovarian cancer. Methods Tumor tissue of 116 consecutive patients diagnosed with primary epithelial ovarian cancer between 1986 and 1995 was analyzed immunohistochemically for HER3 expression. A possible influence of HER3 expression on survival was studied by multivariate Cox regression adjusting for established clinical prognostic factors. Results A positive HER3 expression was observed in 53.4% of the patients. HER3 expression was associated with decreased survival in proportional hazard modeling, including the International Federation of Gynecology and Obstetrics (FIGO) stage, histologic grade and type, residual disease, and age. After likelihood ratio forward as well as backward selection, only HER3 expression (hazard ratio, 1.71; 95% CI, 1.10 to 2.67; P = .018), FIGO stage (hazard ratio, 4.78; 95% CI, 1.89 to 12.08; P = .001), residual tumor (hazard ratio, 2.69; 95% CI, 1.40 to 5.17; P = .003), and age (hazard ratio, 2.06; 95% CI, 1.17 to 3.65; P = .013) were found to be significant. Kaplan-Meier plots demonstrated a clear influence of HER3 expression on survival time. Median survival time was 3.31 years (95% CI, 1.93 to 4.68) for patients with low HER3 expression, compared with only 1.80 years (95% CI, 0.83 to 2.78) for patients with HER3 overexpression (log-rank test P = .0034). Conclusion HER3 may represent a new prognostic factor in primary epithelial ovarian cancer. Pending validation, exploration of therapeutic strategies to block HER3 could be warranted.

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Li, Zhuolin, Chengzhang Shang, Gao An, Chaoshe Guo, W. Frank An e Yi Yang. "Abstract 2619: A novel EGFR × HER3-targeting bispecific antibody drug-conjugate, BCG019, demonstrates robust anti-tumor efficacy in preclinical evaluation". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 2619. http://dx.doi.org/10.1158/1538-7445.am2024-2619.

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Abstract EGFR and HER3 are receptor tyrosine kinases that are highly expressed in multiple epithelial tumors. EGFR point mutations and small insertions within the kinase domain are common in lung cancer. HER3 is overexpressed in patients who are resistant to EGFR-TKI therapy, and is one of the common resistance mechanisms of EGFR and HER2-targeted therapy. We hypothesize that simultaneous targeting of EGFR and HER3 with a bispecific ADC will have the potential to overcome the resistance caused by HER3 after EGFR-targeted therapy and obtain better efficacy than the combination of EGFR monotherapy and HER3 monotherapy. We first generated fully human bispecific antibodies (bsAbs) targeting EGFR and HER3 using RenLite® mice, which contain the full human heavy chain variable domain with a common human kappa light chain to facilitate bispecific antibody assembly. The anti-EGFR × HER3 bsAb demonstrated reactivity to human and cynomolgus monkey antigens and binding to multiple cancer cell lines, including NSCLC, gastric, pancreatic, colorectal, and breast cancer cell lines. The anti-EGFR × HER3 bsAb also showed high internalization activity in cell lines expressing EGFR and HER3. The anti-EGFR × HER3 bsAb was then conjugated with vc-MMAE (valine-citrulline-monomethyl auristatin E) for proof-of-concept studies, as well as BLD1102, Biocytogen’s novel, proprietary linker/payload system composed of a DNA Topo I inhibitor payload (BCPT02) and highly hydrophilic protease-cleavable linker, to generate EGFR- and HER3-targeting bispecific ADC candidates BCG019. In vivo efficacy of the bsADC candidates were evaluated in cell-derived NSCLC and gastric cancer xenografts and in patient-derived gastric and colorectal xenograft models. Both bsADCs showed superior anti-tumor activity when compared to benchmark ADCs. Collectively, these results suggest that our novel anti-EGFR × HER3 bsADC has therapeutic potential for EGFR and HER3 co-expressing tumors. Citation Format: Zhuolin Li, Chengzhang Shang, Gao An, Chaoshe Guo, W. Frank An, Yi Yang. A novel EGFR × HER3-targeting bispecific antibody drug-conjugate, BCG019, demonstrates robust anti-tumor efficacy in preclinical evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2619.

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Cruz, Rodrigo G. B., Stephen F. Madden, Cathy E. Richards, Sri HariKrishna Vellanki, Hanne Jahns, Lance Hudson, Joanna Fay et al. "Human Epidermal Growth Factor Receptor-3 Expression Is Regulated at Transcriptional Level in Breast Cancer Settings by Junctional Adhesion Molecule-A via a Pathway Involving Beta-Catenin and FOXA1". Cancers 13, n. 4 (19 febbraio 2021): 871. http://dx.doi.org/10.3390/cancers13040871.

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The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.

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Satake, Tomoyuki, Chigusa Morizane, Mao Okada, Mariko Nishioka, Nobuyoshi Hiraoka, Satoshi Nara, Tomoya Kakegawa et al. "Abstract 3405: Changes in HER3 expression associated with chemotherapy for pancreatic cancer". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 3405. http://dx.doi.org/10.1158/1538-7445.am2023-3405.

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Abstract Background: Currently, intense efforts towards the development of targeted therapy, including anti-HER3 strategies for cancer treatment, are being made. Recently, HER3 activation was linked to resistance to targeted therapies (EGFR/HER2/MEK/RAF) and hormonal therapy by upregulating HER3 expression after those treatments in several cancer types. However, HER3 expression profile in pancreatic cancer treatment is still unknown. Here, we evaluated the status of HER3 expression after chemotherapy for pancreatic cancer. Methods: Patients with pancreatic cancer who underwent chemotherapy between January 2010 and June 2020 and from whom post-treatment archival tissue specimens were collected were included in this study. All resectable and locally advanced cases were evaluated using resected specimens, and all metastatic cases were evaluated using biopsy specimens. In patients from whom both pre- and post-chemotherapy specimens were collected, changes in HER3 expression status before and after treatment were immunohistochemically evaluated by using HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology) as a primary antibody. IHC scoring (0, 1+, 2+, 3+) of membranous staining intensity was performed according to HER2 IHC gastric scoring guideline. Results: Post-chemotherapy HER3 expression was evaluable in 41 patients, comprising 12, 14, 14, and 1 case as HER3 3+, 2+, 1+ and 0, respectively. In the HER3 3+/2+ and 1+/0 groups, tumor localization was 69%/67% in the pancreatic head, 23%/13% in the pancreatic body, and 8%/20% in the pancreatic tail; tumor stage was resectable (post-neoadjuvant status) 46%/20%, locally advanced 42%/47%, and metastatic 12%/33%; the median tumor size was 30 mm/35 mm; CEA elevation was 23%/20% and CA19-9 elevation was 69%/73%; treatment regimens were FOLFIRINOX 23%/40%, gemcitabine + nab-paclitaxel 19%/0%, gemcitabine + S-1 (neoadjuvant setting) 42%/27%, and the other chemotherapy 4%/20%, respectively. HER3 expression was able to be evaluated before and after chemotherapy in 5 cases: HER3 IHC score changed from 3+/2+ to 1+/0 for 1 case, from 1+/0 to 3+/2+ for 1 case and maintained at 3+/2+ for 3 cases. The median overall survival was 19.6 and 20.5 months in the HER3 3+/2+ and HER3 1+/0 groups, respectively (P = 0.965). Conclusion: HER3 expression with 3+/2+ is observed in 63% of pancreatic cancer patients, and HER3-expressing pancreatic cancer is of great interest as a therapeutic target. HER3 expression status may change before and after cytotoxic combination therapy in some cases of pancreatic cancer. Citation Format: Tomoyuki Satake, Chigusa Morizane, Mao Okada, Mariko Nishioka, Nobuyoshi Hiraoka, Satoshi Nara, Tomoya Kakegawa, Maki Kobayashi, Kumiko Koyama, Minoru Esaki, Takuji Okusaka. Changes in HER3 expression associated with chemotherapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3405.

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Lim, Malcolm, Tam H. Nguyen, Colleen Niland, Lynne E. Reid, Parmjit S. Jat, Jodi M. Saunus e Sunil R. Lakhani. "Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases". Cancers 14, n. 3 (21 gennaio 2022): 533. http://dx.doi.org/10.3390/cancers14030533.

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HER2+ breast cancer patients have an elevated risk of developing brain metastases (BM), despite adjuvant HER2-targeted therapy. The mechanisms underpinning this reduced intracranial efficacy are unclear. We optimised the in situ proximity ligation assay (PLA) for detection of the high-affinity neuregulin-1 receptor, HER2-HER3 (a key target of pertuzumab), in archival tissue samples and developed a pipeline for high throughput extraction of PLA data from fluorescent microscope image files. Applying this to a large BM sample cohort (n = 159) showed that BM from breast, ovarian, lung and kidney cancers have higher HER2-HER3 levels than other primary tumour types (melanoma, colorectal and prostate cancers). HER2 status, and tumour cell membrane expression of pHER2(Y1221/1222) and pHER3(Y1222) were positively, but not exclusively, associated with HER2-HER3 frequency. In an independent cohort (n = 78), BM had significantly higher HER2-HER3 levels than matching primary tumours (p = 0.0002). For patients who had two craniotomy procedures, HER2-HER3 dimer levels were lower in the consecutive lesion (n = 7; p = 0.006). We also investigated the effects of trastuzumab and pertuzumab on five different heterodimers in vitro: HER2-EGFR, HER2-HER4, HER2-HER3, HER3-HER4, HER3-EGFR. Treatment significantly altered the absolute frequencies of individual complexes in SKBr3 and/or MDA-MB-361 cells, but in the presence of neuregulin-1, the overall distribution was not markedly altered, with HER2-HER3 and HER2-HER4 remaining predominant. Together, these findings suggest that markers of HER2 and HER3 expression are not always indicative of dimerization, and that pertuzumab may be less effective at reducing HER2-HER3 dimerization in the context of excess neuregulin.

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Kurmasheva, Raushan, Peter Houghton, Vanessa Del Pozo, Samson Ghilu, Ryuichi Nakamura, Pang-Dian Fan, Emily Jocoy et al. "Abstract 1088: An evaluation of patritumab deruxtecan (HER3-DXd, U3-1402) against pediatric PDX models for hepatoblastoma and rhabdomyosarcoma - A report from the NCI PIVOT Program". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 1088. http://dx.doi.org/10.1158/1538-7445.am2024-1088.

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Abstract Introduction: HER3-DXd is an ADC consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload (DXd, an exatecan derivative) that has demonstrated clinically meaningful efficacy with durable responses in adults with non-small cell lung cancer. Two childhood cancers with HER3 expression are rhabdomyosarcoma (RMS) and hepatoblastoma (HB), and the goal of this work was to evaluate the activity of HER3-DXd against PDX models for these cancer types. Methods: IHC testing was conducted on FFPE tissue (slides or TMA) using HER3/ErbB3 (D22C5) XP rabbit mAB and membrane expression was determined. HB models were evaluated using HER3-DXd and control IgG ADC (C-ADC) with a DXd payload, both at 10 mg/kg weekly x 3. RMS models were evaluated using HER3-DXd and C-ADC at 3 mg/kg and 10 mg/kg administered weekly x 3. Activity was assessed by the PIVOT objective response measure (ORM) targeting partial, complete, or maintained complete responses (PR, CR, and MCR) as compared to stable disease (SD) or progressive disease, with or without growth delay (PD2 and PD1, respectively). Results: For 11 HB models, HER3 expression was 0 (n=2), 1+ (n=5), 2+ (n=1), and 3+ (n=3). For 8 RMS models, median IHC scores were 0 (n=1), 1+ (n=5), and 2+ (n=2). HER3-DXd activity by ORM is shown in the table. Three of 4 HB models treated with HER3-DXd showed MCR, while one had PD. The 3 HB models with MCR responses to HER3-DXd showed lesser responses to C-ADC. HER3-DXd was highly active against RMS models at 3 and 10 mg/kg with most models having MCR. C-ADC was also highly active against RMS models at both dose levels. At 10 mg/kg HER3-DXd, 2 of 4 HB models and 3 of 6 evaluable RMS models had time to event > 100 days. Conclusions: Many HB and RMS models show HER3 expression by IHC. HER3-DXd is highly active against both HB and RMS models. The high activity of C-ADC for RMS models suggests exquisite sensitivity of RMS models to the DXd payload Treatment response categories to treatment of pediatric PDX models with HER3-Dxd PD1 PD2 SD PR CR MCR HB (HER3-Dxd, 10 mg/kg) 1 - - - - 3 HB (C-ADC, 10 mg/kg) 2 1 - 1 - - RMS (HER3-Dxd, 3 mg/kg) - 1 - - - 5 RMS (C-ADC, 3 mg/kg) - - - 1 2 2 RMS (HER-Dxd, 10 mg/kg) - - - - - 6 RMS (C-ADC, 10 mg/kg) - - - - 2 4 Citation Format: Raushan Kurmasheva, Peter Houghton, Vanessa Del Pozo, Samson Ghilu, Ryuichi Nakamura, Pang-Dian Fan, Emily Jocoy, Tim Stearns, Steve Neuhauser, Jeff Chuang, Carol J. Bult, Beverly A. Teicher, Malcolm A. Smith. An evaluation of patritumab deruxtecan (HER3-DXd, U3-1402) against pediatric PDX models for hepatoblastoma and rhabdomyosarcoma - A report from the NCI PIVOT Program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1088.

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Bawa, I. Gusti Agung Gede, Sri Rahayu Santi, Wiwik Susanah Rita, Olan Suryanadi e Gek Indyan. "Active compounds of Michelia champaca bark extract against Curvularia verruculosa fungi causing leaf spot disease in rice (Oryza sativa L.)". Journal of Applied and Natural Science 16, n. 1 (20 marzo 2024): 420–26. http://dx.doi.org/10.31018/jans.v16i1.5406.

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Curvularia verruculosa fungal causes leaf spot disease in rice plants. The bark extract of Michelia champaca could inhibit the growth of the fungi. The present research aimed to know the active compound responsible for antifungal activity. Extraction was done using the Maceration method, antifungal activity was measured using the Diffusion well method, and identification of active compounds was carried out using Gas chromatography-mass spectroscopy (GC-MS). The methanol extract obtained had a yield of 18.7%. It showed strong activity against C. verruculosa with an inhibition zone until 30.01 mm. The fractionation results showed that n-hexane extract (HE) was the strongest inhibiting the growth of C. verruculosa (32.45 mm), followed by chloroform extract (CE) (29.20 mm), while n-butanol extract (BE) was not active. Separating active compounds from HE extract was made using Column chromatography (CC) method with silica gel as the stationary phase and the mixture of n-hexane-acetone (3:1) as the mobile phase. This separation resulted in 5 combined fractions; HE3 and HE5 extracts showed very strong activity against C. verruculosa, with a diameter of the inhibition zone of 26.73 and 33.46 mm, respectively; HE2 extract showed strong activity with a diameter of the inhibition zone of 15.21 mm, while HE1 and HE4 extracts did not show activity. Identification using GC-MS, especially the HE3 extract, revealed that the extract contained two compounds: tributyl acetyl citrate and terephthalic acid, dodecyl-2-ethylhexyl ester. The result indicated that the bark extract of M. champaca had the potential to be a botanical fungicide.

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Romaniello, Donatella, Ilaria Marrocco, Nishanth Belugali Nataraj, Irene Ferrer, Diana Drago-Garcia, Itay Vaknin, Roni Oren et al. "Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor". Cancers 12, n. 9 (24 agosto 2020): 2394. http://dx.doi.org/10.3390/cancers12092394.

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Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational downregulation of HER3, suppression of MET and AXL upregulation, as well as concomitant inhibition of AKT signaling and upregulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing.

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Jacobs, Bart, Loredana Vecchione, Nicholas Hoe, Jef De Schutter, Bart Biesmans, Sharat Singh e Sabine Tejpar. "Effect of EGFR inhibition on HER3/PI3K activation by feedback induction of ErbB heterodimers in cetuximab-sensitive colon cancer cells." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): 3626. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3626.

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3626 Background: Although cetuximab treatment has been successful for the treatment of KRAS wild-type colorectal cancers, complete remissions are rarely seen in patients, leading ultimately to resistance. We hypothesized that in cetuximab-sensitive patients, the ErbB network is insufficiently targeted since network plasticity may occur. Methods: We have used EGFR-sensitive colorectal cancer cells and investigated ErbB network activity and adaptations by RTK arrays, western blot, and Collaborative Enzyme Enhance Reactive immunoassay (CEER). These were complemented by ErbB heterodimerization (HER2:3, HER1:2, HER1:3, HER3:PI3K) assays using CEER. Effects on cell survival were measured using colony formation assay. In addition to the EGFR sensitive cell line, 200 clinical colorectal cancer (CRC) samples were profiled utilizing CEER for RTKs, downstream signaling, and heterodimerization. Results: EGFR and downstream signaling proteins AKT, ERK, and RSK were potently inhibited by cetuximab or gefitinib at 24h of treatment in EGFR sensitive colorectal cancer cell line. At 24h of treatment, we observed approximately 2 folds increase in total HER2 and HER3 protein levels, 2.7 folds in phosphorylated HER3, and 5.4 folds in HER2:HER3 heterodimer formation. Concurrently, increased in ErbB heterodimer formation was accompanied by 5 folds increase in PI3K binding to HER3, resulting in enhanced HER3 signaling, with increase in AKT, ERK, and RSK. Co-treatment of these cells with cetuximab and HER2 inhibitor Trastuzumab or by treatment with lapatinib blocked the induction of HER2:HER3 heterodimer, HER3 phosphorylation, and PI3K binding to HER3. In 30% of the 200 clinical colorectal cancer samples profiled, we observed an increased in phosphorylated HER3, formation of HER2:HER3 and HER3:PI3K heterodimers along with HER1 activation (KRAS WT). Conclusions: Combination of HER2 inhibitor with an EGFR inhibitor could potentially increase the therapeutic index in cetuximab sensitive patients, and suppress activation of feedback mechanisms upon EGFR inhibition. Current findings suggest that CRC patients with similar profile would benefit from these combination therapies.

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Park, Yeon Hee, Hyun Ae Jung, Won Jin Chang, Moon Ki Choi, Jung Yong Hong, Oh-Nam Ok, Jeong Ju Seo et al. "Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) patients who received taxane plus trastuzumab treatment." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): 637. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.637.

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637 Background: The HER3 receptor is a key member of ErbB family and preferentially signals through the PI3K pathway. Formation of dimers between HER3 and HER2 seems to be crucial for HER2-driven signals in HER2 overexpressing tumors. Given the fact that HER2-HER3 is considered the most active signalling dimer of the ErbB system, HER3 activity may contribute to the resistance of trastuzumab. PTEN plays a well-established role in the negative regulation of the PI3K pathway. Our aim of this study was to investigate the role of HER3 and PTEN expression in patients with HER2 overexpressed MBC. Methods: One-hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as the first line therapy were included in this analysis. Immunohistochemical stainings (IHC) with HER3 and PTEN antibody were conducted retrospectively. Results: Median age was 48 years. HER3 IHC was graded from 0 to 3. PTEN IHC was scored as multiplication of intensity and proportion from 0 to 300. The patients who had negative HER3 stain showed better progression free survival (PFS) to taxane plus trastuzumab chemotherapy than those positive HER3 stain (p=0.001, median PFS 21 vs. 11 mo.). The patients who had PTEN score of more than 20 showed longer PFS than those PTEN score of 20 or less than 20 (p=0.006, median PFS 13 vs. 9 mo.). The patients who had PTEN score of more than 20 showed longer overall survival (OS) than those PTEN score of 20 or less than 20 (p=0.005, median OS 48 vs. 25 mo.). HER3 negativity and PTEN loss were identified as independent risk factors for PFS [Hazard Ratio (HR) 0.4 (95% CI 0.3-0.8 for HER3 negativity; HR 2.1 (95% CI 1.2-3.7) for PTEN loss]. However, PTEN loss (HR 3.1 [95% CI 1.6-6.3]) was identified as an independent risk factor for OS. Conclusions: HER3 and PTEN expression may be predictive markers for trastuzumab treatment in HER2-positive MBCs. PTEN expression may have a potential predictive and prognostic biomarker for trastuzumab treatment.

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Kilroy, Mary K., Rosalin Mishra, Anastasia Stupecki, Wasim Feroz, Samar Alanazi e Joan T. Garrett. "Abstract 3988: The role of HER3 mutations in the progression of colon cancer and modulation of drug sensitivity and resistance". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 3988. http://dx.doi.org/10.1158/1538-7445.am2023-3988.

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Abstract Colorectal cancer is a disease of the colon and rectum that will claim about 52,580 American lives in2022. The most common treatment of colorectal cancer is surgery plus chemotherapy, although thereare some FDA approved targeted therapies such as regorafenib (targeting VEGF) or cetuximab (targetingEGFR). EGFR, along with HER2, HER3, and HER4 are members of the HER family of receptor tyrosinekinases that upon homo- or heterodimerization activate downstream signaling, growth, and survivalpathways. In recent years, more attention has been paid to HER2 and HER3’s roles in colorectal cancers,as they may cause resistance to targeted therapies. OWe are investigating naturally occurring mutantHER3’s role in colorectal cancer, as about 6% of all colorectal cancers contain a HER3 mutation. We arecurrently investigating how HER3 mutations may affect sensitivity to current therapies through HERfamily receptor dimerization and be involved in tumor metastasis. We are assessing the degree to whichmutant and wild-type HER3 have the ability to dimerize with EGFR, HER2, MET, and IGF1R the resultingeffects in colon cancer, as these receptor tyrosine kinases are HER3 binding partners. As HER3 bindingpartners are diverse, it may be that the pathway HER3 and its binding partner activate may influencetreatment strategy. It has been noted that mutant HER2 and HER3 could confer sensitivity to HER familyinhibitors, i.e. afatinib, in bladder cancer, and we have seen a difference in IC50 values of afatinibbetween cell lines containing wild-type or mutant HER3. If mutant HER3 is involved in therapeuticresistance or sensitivity and tumor progression, our findings may present a new biomarker for targetedtreatments in colorectal cancer with the eventual goal of increased overall patient survival. Citation Format: Mary K. Kilroy, Rosalin Mishra, Anastasia Stupecki, Wasim Feroz, Samar Alanazi, Joan T. Garrett. The role of HER3 mutations in the progression of colon cancer and modulation of drug sensitivity and resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3988.

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Rathore, Moeez Ghani, Kimberly Curry, Christina Boutros, Zhenghe Wang, Jordan Winter e Rui Wang. "Abstract 3082: The liver microenvironment promotes glycolysis in metastatic colorectal cancer by activating her3". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 3082. http://dx.doi.org/10.1158/1538-7445.am2024-3082.

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Abstract Background: Liver metastasis occurs in ~80% of all metastatic colorectal cancer (mCRC) and the liver has a unique endothelial cell (EC)-rich microenvironment that promotes cancer cell survival. We previously reported that liver ECs secrete soluble factors to promote CRC growth via activating CRC-associated the HER3 signaling pathway. The present study reports that ECs promote mCRC growth by shifting cancer metabolism towards glycolysis and elucidates the involved signaling pathway. Methods: We performed mass spectrometry to profile the metabolic changes in mCRC treated with/without HER3 inhibition in a syngeneic, orthotopic mCRC model. We also performed Seahorse and lactate ELISA assays to determine the effect of liver EC-secreted factors on CRC metabolism. To further determine the role of HER3 in promoting glycolysis and CRC growth in the liver, we used siRNA silencing of HER3 and pharmacological inhibition of HER3 downstream signaling proteins to identify the key mediator(s) of HER3-induced metabolic shift in CRC. Results: We determined that HER3 inhibition leads to increased oxidative phosphorylation metabolites (OXPHOS) and decreased glycolysis metabolites in CRC liver metastases. Conditioned medium containing EC-secreted factors decreased oxygen consumption (determined by Seahorse, a readout of OXPHOS) and increased lactate secretion (determined by ELISA, a readout of glycolysis) in CRC. As HER3 inhibition reversed the metabolic shift and increased OXPHOS as an alternative survival strategy, we found that simultaneous inhibition of HER3 and OXPHOS synergistically blocked CRC cell and tumor growth. Lastly, we found that PFK2 is activated by HER3 signaling, determined by phosphorylation, and determined that the HER3-AKT-PFK2 signaling axis is the key mediator of EC-induced metabolic shifts. Conclusions: We identified that the liver microenvironment activates HER3 and the downstream AKT-PFK2 signaling to promote glycolysis and growth in CRC liver metastases by activating AKT-PFK2-dependent glycolysis. Our findings highlighted the potential of combining HER3 and OXPHOS inhibitions as a potential strategy for treating patients with mCRC. Citation Format: Moeez Ghani Rathore, Kimberly Curry, Christina Boutros, Zhenghe Wang, Jordan Winter, Rui Wang. The liver microenvironment promotes glycolysis in metastatic colorectal cancer by activating her3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3082.

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Raghav, Kanwal Pratap Singh, Takayuki Yoshino, Hiroya Taniguchi, Sabine Tejpar, Arndt Vogel, Zev A. Wainberg, Kensei Yamaguchi et al. "An open-label, phase II study of patritumab deruxtecan (HER3-DXd, U3-1402) in patients (pts) with previously treated advanced/metastatic colorectal cancer (CRC)." Journal of Clinical Oncology 39, n. 3_suppl (20 gennaio 2021): TPS157. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.tps157.

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TPS157 Background: Patritumab deruxtecan (HER3-DXd; U3-1402) is a novel, investigational antibody drug conjugate comprising an anti-HER3 monoclonal antibody, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload. Ongoing clinical trials of HER3-DXd in pts with metastatic breast cancer or non-small cell lung cancer have shown promising clinical activity and acceptable safety. HER3 (human epidermal growth receptor 3), a member of the tyrosine kinase receptor family, is overexpressed in most CRC tumors and associated with an adverse prognosis. Significant tumor regression with HER3-DXd has been observed in CRC murine xenograft models, regardless of KRAS mutation status. Here we introduce the design of a phase 2 study (U31402-A-U202) that is evaluating HER3-DXd in previously treated pts with advanced/metastatic CRC. Methods: U31402-A-U202 (NCT04479436) is an open-label, multicenter phase 2 study that will enroll 80 pts in the USA, Europe and Asia. Pts are enrolled who are aged ≥ 18 years with advanced/metastatic colorectal adenocarcinoma that is resistant/refractory/intolerant to ≥ 2 prior lines of therapy including a fluoropyrimidine, irinotecan, a platinum agent, an anti-EGFR agent (if clinically indicated), an anti-VEGF agent (unless contraindicated [CI]), and an immune checkpoint inhibitor (unless CI) for microsatellite instability-high CRC. Pts with current/previous interstitial lung disease or clinically severe pulmonary compromise are excluded. Archival tumor biopsy and pre-treatment tumor biopsy are collected from all pts at screening, with HER3 protein expression measured by immunohistochemistry (IHC). In part 1, results of the HER3 IHC assay from the pre-treatment tumor biopsy are used to assign pts into 1 of 2 cohorts (C). C1: HER3 high (IHC 3+, 2+), n = 24; C2: HER3 low/negative (IHC 1+, 0), n = 12. Pts receive 5.6 mg/kg HER3-DXd IV every 3 weeks. An interim futility analysis will be conducted separately for C1 and C2 and will determine enrollment in part 2, with 2 potential scenarios: enrollment continues irrespective of HER3 IHC status, or enrollment continues in HER3 high pts only. The primary objective is the evaluation of the antitumor activity of HER3-DXd as measured by objective response rate (ORR) (assessed by BICR according to RECIST v1.1). ORR will be summarized with the 2-sided 95% confidence interval. Secondary objectives include the evaluation of efficacy as measured by ORR (assessed by investigator according to RECIST v1.1), duration of response, time to tumor response, disease control rate, progression-free survival (assessed by investigator and BICR according to RECIST v1.1), overall survival, safety and tolerability, HER3 protein expression in tumor tissue and relationship with efficacy, and pharmacokinetic properties. Clinical trial information: NCT04479436.

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Kilroy, Mary K., Briley Park, Rosalin Mishra, Wasim Feroz, Cecilia Wischmeier e Joan T. Garrett. "Abstract 7150: Molecular insights into the oncogenic influence between mutant HER3, mutant KRAS, and their synergistic interplay in colorectal cancer pathogenesis". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 7150. http://dx.doi.org/10.1158/1538-7445.am2024-7150.

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Abstract Colorectal cancer (CRC) is a disease of the colon and rectum that will claim about 52,550 American lives in 2023. In recent years, more attention has been paid to HER2 and HER3’s roles in colorectal cancers, as they may cause resistance to targeted therapies. We are investigating the role of naturally co-occurring HER3 and KRAS mutations in colorectal cancer, as about 6% of all colorectal cancers contain a HER3 mutation and 41% contain a KRAS mutation. We have observed that there is a statistically significant co-occurrence of HER3 and KRAS mutations in CRCs while there is mutual exclusivity with mutations in EGFR or HER4 and mutant KRAS in CRC examining 6791 samples from 17 studies. There is a tendency for co-occurrence with HER2 and KRAS mutations that is not statistically significant in these CRC tumor samples. We have found that genetic knockdown of both KRAS and HER3 with siRNA targeting KRAS and HER3 in the CRC cell line SNU-407 (HER3V104M, KRASG12D) results in a statistical reduction in cell proliferation in comparison to genetic knockdown with only KRAS or HER3. Using the SW620 CRC cell line (HER3WT, KRASG12V) as a comparison, we have observed that knocking down HER3 using siRNA had no effect on cell proliferation whereas KRAS knockdown reduced proliferation and the combination showed no statistical difference compared to knocking down only KRAS. Additionally, we have found that there is a striking increase in total HER3 levels in SNU-407 cells when treated with the KRASG12D inhibitor MRTX1133. This feedback loop could limit the efficacy of the KRAS inhibitor. We wished to delineate mutant HER3’s binding partner(s) as HER3 is kinase impaired. Strikingly, we have found that EGFR immunoprecipitates with HER3 in SNU-407 cells. We are expanding our studies to CRC patient derived xenografts (PDXs) with co-occurring HER3 and KRAS mutations and have generated patient derived organoids from these PDXs. Ongoing studies are determining if there is a synergistic relationship with KRAS inhibitors and HER family inhibitors including a HER3 antibody-drug conjugate. Our findings may present a new paradigm for targeted combination therapies in colorectal cancer with the eventual goal of increased overall patient survival. Citation Format: Mary K. Kilroy, Briley Park, Rosalin Mishra, Wasim Feroz, Cecilia Wischmeier, Joan T. Garrett. Molecular insights into the oncogenic influence between mutant HER3, mutant KRAS, and their synergistic interplay in colorectal cancer pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7150.

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Wang, Lina, Meijun Xiong, Xinju Gao, Chengang Zhou, Yu Han, Yanchun Li, Junhao Wang, Lili Shi, Gang Qin e Paul H. Song. "Abstract 2114: Enhancing therapeutic strategies for osimertinib-resistant EGFR-mutant NSCLC: A HER3 dual-payload ADC (dpADC) with topoisomerase I and EGFR tyrosine kinase inhibitor". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 2114. http://dx.doi.org/10.1158/1538-7445.am2024-2114.

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Abstract Background: EGFR tyrosine kinase inhibitors (TKIs) have significantly improved the survival rate and the quality of life of the NSCLC patients with EGFR mutation in the first line setting. For example, Osimertinib, a potent third-generation EGFR TKI, has demonstrated exceptional efficacy in metastatic NSCLC with specific EGFR mutations. Despite its success, the emergence of drug resistance, often linked to elevated HER3 protein expression, remains a significant challenge. U3-1402 (HER3-Dxd), an HER3 ADC, demonstrates a promising result in managing Osimertinib-resistant NSCLC. It has been reported that combining U3-1402 with Osimertinib has shown enhanced efficacy in resistant cell lines and mouse models. Here, we explore a novel HER3 dual-payload ADC (HER3 dpADC), uniquely combining a Topoisomerase I inhibitor and an EGFR TKI within a single antibody structure using the enzymatic site-specific conjugation platform developed by GeneQuantum (GQ). This innovative approach demonstrates potent and synergistic anti-tumor effects in vitro and in vivo, presenting an alternative therapeutic strategy for EGFR-mutant NSCLC patients. Results: GQ's dpADC platform technology employs two orthogonal enzymatic site-specific conjugations and stable linker technologies to efficiently generate the dual-payload ADC with high homogeneity and quality. For HER3 dpADC, HER3 Ab was conjugated with a novel Topoisomerase I inhibitor, TopoIx, and an EGFR tyrosine kinase inhibitor. In vitro DAR analysis revealed high linker stability, with minimal free payload release even after 96 hours of plasma incubation. Binding affinity assessments confirmed comparable affinity between HER3 dpADC and HER3 mAb in specific EGFR exon 19 deletion cell lines. Using various NSCLC cell lines in a 3D-spheroid culture system, HER3 dpADC demonstrated significant dose-dependent and synergistic anti-tumor activities. A robust bystander killing efficacy was observed in both HER3+/HER3- HEK293T cell coculture assays. Evaluation in CDX mouse models consistently demonstrated heightened in vivo efficacy by HER3 dpADC, aligning with the promising in vitro data. In NSCLC patient-derived xenograft (PDX) mouse models representing EGFR tyrosine kinase inhibitor-sensitive or resistant phenotypes, HER3 dpADC induced tumor regressions with no obvious toxicity, underscoring its potential as the next-generation HER3 targeting agent. Conclusion: The innovative HER3 dpADC, leveraging an efficient dual enzymatic site-specific conjugation, exhibited robust anti-tumor efficacy in both in vitro and in vivo settings, surpassing single-agent treatments. Its synergistic mechanism of action presents a promising possibility for developing a more potent and the front-line therapeutic solutions in NSCLC patients who have progressed on standard therapies. Citation Format: Lina Wang, Meijun Xiong, Xinju Gao, Chengang Zhou, Yu Han, Yanchun Li, Junhao Wang, Lili Shi, Gang Qin, Paul H. Song. Enhancing therapeutic strategies for osimertinib-resistant EGFR-mutant NSCLC: A HER3 dual-payload ADC (dpADC) with topoisomerase I and EGFR tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2114.

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Bartsch, Rupert, Anna Sophie Berghoff, Zsuzsanna Bago-Horvath, Matthias Preusser, Guenther G. Steger, Margareta Rudas, Peter Birner e Christoph Zielinski. "Coexpression of HER3 as a predictor of survival in HER2-positve breast cancer patients." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): 611. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.611.

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611 Background: Improved understanding of the pathobiology of the metastatic cascade as well as the identification of new prognostic markers may lead the path to the development of novel targeted agents in breast cancer patients (BC pts). Recently, HER3-expression was postulated as independent risk factor for metastatic spread. Methods: Pts of different BC subtypes (luminal, HER2-amplified, triple-negative) with metastatic disease were identified from a breast cancer data base. Tissue of the primary tumor was retrieved from the local pathology institute. Immunohistochemical staining of estrogen-receptor, progesterone-receptor, and HER2 and HER3 was performed. In HER2 equivocal cases, subsequent FISH analysis was performed. Results: Specimens of 110 pts (36/110 luminal, 35/110 HER2-amplified, 40/110 triple-negative) were available for this analysis. 23/110 (21%) specimens showed strong, complete, membranous staining for HER3 of at least 10% of all tumor cells. HER2/HER3 co-expression was observed in 12/110 (11%) specimens. HER3 showed a statistically significant association with HER2-expression (p=0.02; Chi square test). No correlation was observed for HER3-expression and overall survival (OS), incidence of brain metastases, or time to diagnosis of brain metastases in the entire patient cohort (p>0.05; log rank). In the HER2-amplified subgroup, however, HER3-expression was significantly associated with shorter OS (median 30 vs. 63 months; p=0.02; log rank test) and remained significant when entered into a multivariate model (p=0.02; Cox regression). Conclusions: HER2/HER3 co-expression is significantly associated with impaired OS in pts with HER2-positive metastatic breast cancer. Co-inhibition of HER2 and HER3 or inhibition of HER2/HER3 hetero-dimerization could improve prognosis of this patient population.

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Al-Akhrass, Hussein, James R. W. Conway, Annemarie Svane Aavild Poulsen, Ilkka Paatero, Jasmin Kaivola, Artur Padzik, Olav M. Andersen e Johanna Ivaska. "A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance". Oncogene 40, n. 7 (8 gennaio 2021): 1300–1317. http://dx.doi.org/10.1038/s41388-020-01604-5.

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AbstractCurrent evidence indicates that resistance to the tyrosine kinase-type cell surface receptor (HER2)-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling and the regulation of the dimer is essential to decipher therapy relapse mechanisms. Here, we investigate a bidirectional relationship between HER2-HER3 signaling and a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA; SORL1). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model.

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Alanazi, Samar M., Rosalin Mishra, Hima Patel, Mary K. Kilroy e Joan T. Garrett. "Abstract 5661: HER2 inhibition increases non-muscle myosin IIa to promote tumorigenesis in HER2+ breast cancers". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 5661. http://dx.doi.org/10.1158/1538-7445.am2022-5661.

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Abstract HER2 is amplified in about 20% of breast cancers. HER3 is as essential as HER2 for maintaining cell viability in HER2+ breast cancer cells. It is known that inhibition of HER2 tyrosine kinase activity results in upregulation of HER3 transcription and phosphorylation. We sought to identify HER3 binding partners upon pharmacological inhibition of HER2 using neratinib. We immunoprecipitated HER3 using a HER3 antibody from BT474 cells treated ± neratinib. Fmass spectrometry experiments identified non-muscle myosin IIA (NMIIA) increased upon inhibition of HER2 with neratinib and decreased under DMSO control treatment from HER3 immunoprecipitates. To validate the presence of NMIIA, we performed immunoprecipitation experiments in BT474 and MDA-MB-453 cells using a HER3 antibody. Immunoblots showed increased NMIIA levels upon treatment with 200nM neratinib for 24 hours in both cell lines. Myosin heavy chain 9 (MYH9) gene encodes a protein called non-muscle myosin of class II, isoform A (NMIIA). It localizes to actin stress fibers and has been implicated in many cell functions. To confirm the interaction between HER3 and NMIIA we immunoprecipitated NMIIA from BT474 and MDA-MB-453 cells using a NMIIA antibody. Immunoblots indicated that HER3 levels were increased upon inhibition of HER2 with 200 nM neratinib for 24 hours. We next examined overall survival of primary breast cancer patients who have high gene expression for MYH9 from the METABRIC cohort. We observed that patients with high levels of MYH9 have a statistically significant worse overall survival versus patients with low levels of MYH9. Furthermore, we evaluated the overall levels of HER3 and MYH9 mRNA and protein upon treatment with neratinib in BT474 and MDA-MB-453 whole cell lysates. RT-qPCR and immunoblots showed increased HER3 and NM-IIA mRNA and protein levels upon neratinib treatment for 24 hours We examined the affect NMIIA loss has on HER3 signaling. Transduced MDA-MB-453 and BT474 cells with shMYH9 and doxycycline induction demonstrate a reduction in HER3 protein levels compared to cells transduced with a control sequence and doxycycline induction. We observed a concomitant reduction in P-HER3 (Y1289), downstream P-Akt (T308), and P-Erk1/2. In addition, NM-IIA knockdown suppresses cells growth, proliferation, migration, and invasion. In conclusion, there is a bidirectional relationship between NMIIA and HER signaling in HER2+ breast cancer cells. HER2 inhibition increases NMIIA and NMIIA promotes HER3 expression. Loss of NMIIA reduces HER3 protein and concomitant reductions in PI3K/Akt and MAPK signaling. Loss of NMIIA in combination with HER2 inhibition results in reduction in HER2+ breast cancer cell proliferation, growth on matrigel, migration, and invasion. Studies are ongoing to decipher the mechanisms for the bidirectional relationship between NMIIA and HER signaling. Citation Format: Samar M. Alanazi, Rosalin Mishra, Hima Patel, Mary K. Kilroy, Joan T. Garrett. HER2 inhibition increases non-muscle myosin IIa to promote tumorigenesis in HER2+ breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5661.

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Boutros, Christina S., Alexander W. Loftus, Moeez Rathore, Mehrdad Zarei, Kimberly Curry, Jordan M. Winter e Rui Wang. "Abstract 445: Determining the molecular and biologic effects of HER3 and IDH1 antagonism on liver endothelium-PDAC crosstalk". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 445. http://dx.doi.org/10.1158/1538-7445.am2024-445.

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Abstract INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy due to the lack of early diagnosis and limited response to treatments. Austere and nutrient-deprived conditions typically present in the PDAC tumor microenvironment (TME) induce chemotherapy resistance. Therefore, novel therapeutic strategies are needed. We have previously demonstrated the primary tumor expresses IDH1 which supports the pro-survival oxidative phosphorylation (OXPHOS) metabolism, and has been successfully targeted by ivosidenib, an IDH1 inhibitor, in preclinical studies. Meanwhile, endothelial cells (ECs) from the liver, the most common site of PDAC metastases, secrete soluble factors in the conditioned medium (CM) that activate HER3, a receptor tyrosine kinase, involved in cell proliferation and metabolism. OBJECTIVES: We sought to (1) uncover the mechanisms involved in driving the metabolic differences between primary and metastatic tumors through the utilization of ECs from the liver (2) conduct metabolic analyses to determine metabolic effects of HER3 activation, and (3) examine potential synergism of combination therapy against HER3 and IDH1 in primary and metastatic niches. METHODS: The effect of CM on PDAC cell growth was determined by PICO Green Assay. The effects of ECs HER3/IDH1 inhibitions on cellular metabolism were measured by multiple metabolic assays including Seahorse, CellTiter-Glo, lactate ELISA, and TMRE assays. HER3-specific antibody Seribantumab, HER3 inhibitor Sapitanib, and IDH1 inhibitor ivosidenib were used to block HER3 and/or IDH1. Moreover. A cell viability-based synergy study was performed to assess the effects of HER3-IDH1 combination. Effects of HER3 and IDH1 inhibitions on PDAC tumor growth and mouse survival in vivo were determined in syngeneic, orthotopic models with PDAC primary tumors and liver metastases. RESULTS: CM from liver ECs significantly increased cell growth in PDAC cells in vitro and increased glycolytic tropism in multiple HER3 positive PDAC cell lines measured by metabolic assays mentioned above. HER3 antibody and HER3 inhibitor both increased oxidative consumption rate (OCR), an indirect measure of OXPHOS, and decreased extracellular acidification rate (ECAR), a measure of glycolysis measured by Seahorse. Combination therapy utilizing HER3 and IDH1 inhibitors revealed synergy. In our in vivo tumor model, mice treated with combination therapy had significantly longer overall survival than those given either monotherapy or no treatment. CONCLUSIONS: Our results demonstrated a paracrine role of liver ECs in promoting cell growth via activating HER3 in PDAC cells as well as reprograming cellular metabolism from OXPHOS towards glycolysis. Identification of the metabolic shift that takes place in metastatic PDAC to the liver due to HER3 activation gives way for the development of a potentially lethal drug combination. Citation Format: Christina S. Boutros, Alexander W. Loftus, Moeez Rathore, Mehrdad Zarei, Kimberly Curry, Jordan M. Winter, Rui Wang. Determining the molecular and biologic effects of HER3 and IDH1 antagonism on liver endothelium-PDAC crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 445.

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Kojima, Yuki, Kazuki Sudo, Hiroshi Yoshida, Shu Yazaki, Momoko Tokura, Shosuke Kita, Kasumi Yamamoto et al. "Abstract 5083: Changes in HER3 expression profiles between initial diagnosis and recurrence in gynecologic cancers". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 5083. http://dx.doi.org/10.1158/1538-7445.am2022-5083.

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Abstract Background: HER3 (ErbB-3) is a member of the epidermal growth factor receptor family of receptor tyrosine kinases, and its overexpression is associated with poorer prognosis in several cancer types. It is unclear whether HER3 expression status changes in tumor tissue at relapse. The purpose of this study is to evaluate changes in HER3 expression between initial diagnosis and recurrence in gynecologic cancers. Methods: This retrospective study included gynecologic cancer patients with matched paired tissues at the time of initial diagnosis and at the time of recurrence between 1999 and 2019 at National Cancer Center Hospital, Japan. Immunohistochemical (IHC) staining for HER3 was performed using formalin-fixed paraffin-embedded specimens. The primary antibody was HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology). HER3-positive was defined as an IHC score of 2+ or 3+, and HER3-negative was an IHC score of 0 or 1+, scored according to HER2 testing guidelines for gastroesophageal cancer. The H-score (range, 0-300) was calculated using the following formula: 3X+2Y+Z, where X, Y, and Z are the percentage of tumor cells showing strong, moderate, and weak staining intensity. The difference in HER3 expression between initial diagnosis and recurrence was evaluated using the χ2 test. Results: Eighty-six patients with gynecologic cancers were included (40 ovarian; 32 endometrial; 14 cervical). In ovarian cancer, 67.5% and 80.0% of the patients were HER3-positive at initial diagnosis and recurrence, respectively. There was a statistically significant increase in H-Score at recurrence (p=0.004). The HER3-positive rate in patients with endometrial cancer increased from 46.9% at initial diagnosis to 68.8% at recurrence, and H-Score tended to increase at recurrence (p=0.08). Twelve of the 14 patients (85.7%) with cervical cancer were HER3-positive, both at initial diagnosis and at recurrence, and H-Score tended to increase at recurrence (p=0.19). The discordance rate of HER3 expression determination in samples at initial diagnosis and recurrence was 27.5%, 46.9%, and 14.3% for ovarian, endometrial, and cervical cancers, respectively. Conclusion: Our findings suggest that HER3 expression may increase at recurrence in patients with gynecologic cancers. HER3-targeted therapy may represent a promising option to overcome treatment failure and improve patient outcomes. Citation Format: Yuki Kojima, Kazuki Sudo, Hiroshi Yoshida, Shu Yazaki, Momoko Tokura, Shosuke Kita, Kasumi Yamamoto, Chiharu Mizoguchi, Hitomi S Okuma, Tadaaki Nishikawa, Emi Noguchi, Tatsunori Shimoi, Yasuhito Tanase, Masaya Uno, Mitsuya Ishikawa, Tomoyasu Kato, Kumiko Koyama, Maki Kobayashi, Tomoya Kakegawa, Yasuhiro Fujiwara, Kan Yonemori. Changes in HER3 expression profiles between initial diagnosis and recurrence in gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5083.

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