Articles de revues : « Targeted therapies, RAS, MEK, PI3K »

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LaRue, Rebecca S., Hanh Nguyen, Karen Sachs, Nurul Azyan Mohd Hassan, Ernesto Diaz-Flores, Susan K. Rathe, Aaron G. Sarver et al. « Ras-Pathway Inhibition With Targeted Therapies Abrogates Self-Renewal In Acute Myelogenous Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 819. http://dx.doi.org/10.1182/blood.v122.21.819.819.

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Abstract Hyperactivated Ras-pathways serve as oncogenic drivers in multiple human tumors including acute myelogenous leukemia (AML) (Ahearn et al. Nat Rev Mol Cell Biol 2011). The specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. Recently, we have shown that NRASG12V–activated signaling pathways are critical to leukemia stem cell maintenance (Sachs et al. submitted). To elucidate which Ras-activated signaling molecules mediate self-renewal in AML, we employed a murine model that harbors Mll-AF9 and a tetracycline repressible, activated NRAS (NRASG12V) and develops AML (Kim et al. Blood 2009). Primary leukemia cells were treated with therapeutic agents targeting Ras-activated signaling pathways. We used PD325901 to inhibit the Mek-Erk pathway, GDC0941 to inhibit the Pi3k pathway, and RAD001 to inhibit the mTor pathway. Using MTS assays, we identified the IC50 dose for each of these agents. Inhibitor-treated leukemia cells were submitted for RNA sequencing in order to investigate the effects of these agents on leukemia gene expression. Previously, we identified a list of NRASG12V responsive genes in our model. In these studies, we identified that PD325901-treatment most closely recapitulates the effect of NRASG12V inhibition on this comprehensive list of RAS-responsive genes. However, when we study the effects of these inhibitors on the subset of RAS-responsive genes that mediate leukemia self-renewal, we find that both PD325901 and RAD001 independently recapitulate the effects of NRASG12V withdrawal on this subset of genes implicating the Mek and mTor pathways in leukemia self renewal. Next, we treated primary leukemia cells with the IC50 dose of each drug and plated them in colony forming assays. We found that Mek or mTor inhibition, but not Pi3k inhibition, abrogated secondary colony formation corroborating our gene expression analyses and showing that, at doses that have equivalent effects on cell growth, only the Mek and mTor pathways are important for leukemia cell stem cell maintenance. These studies provide potential targets for leukemia stem cell-specific therapies. Disclosures: Sachs: Silicon Valley Biosystems: Consultancy. Bendall:DVS Sciences: Consultancy. Nolan:SAB for DVS Sciences and Nodality: Chairman Other; Cell Signalling Technologies and Becton Dickenson, Inc: Consultancy. Largaespada:Discovery Genomics, Inc: Consultancy, Share Holder Other; NeoClone Biotechnology, Inc: Consultancy, Share Holder, Share Holder Other.

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Huang, Tannie, Jon Akutagawa, Inbal Epstein, Charisa Cottonham, Maricel Quirindongo-Crespo et Benjamin S. Braun. « Inhibition of Akt Signaling Alleviates MDS/MPN Driven By KrasD12 or Nf1 Loss ». Blood 126, n^o 23 (3 décembre 2015) : 360. http://dx.doi.org/10.1182/blood.v126.23.360.360.

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Abstract Juvenile and chronic myelomonocytic leukemias (JMML and CMML) are aggressive myeloid malignancies categorized as myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN). Chemotherapy has little benefit for MDS/MPN patients, and new therapies are needed. We have used mouse models investigate the potential of signal transduction inhibitors in MDS/MPN, as JMML and CMML are associated with mutations in NRAS, KRAS, PTPN11, CBL, or NF1 that activate Ras signaling. Conditional Mx1-Cre, KrasLSL-D12 (designated KrasD12) mice develop an aggressive and fully penetrant MDS/MPN characterized by leukocytosis, splenomegaly, anemia, and death by 10-16 weeks of age. Mx1-Cre, Nf1flox/- mice (hereafter Nf1Δ/-) undergo conditional loss of Nf1. These mice also develop MDS/MPN, but the disease is more indolent. We and others have investigated inhibition of effector networks downstream of Ras, such as the Raf/MEK/ERK (MAPK) and phosphotidylinositol-3 kinase (PI3K)/Akt pathways. We previously showed that the MEK inhibitor PD0325901 induced sustained hematologic improvement in both KrasD12 and Nf1Δ/- mice. We also have reported that the class I PI3K inhibitor GDC-0941 improves hematologic function and prolongs survival in KrasD12 mice. However, GDC-0941 and other PI3K inhibitors attenuate both PI3K/Akt and Raf/MEK/ERK pathways due to effects of PI3K upstream of Ras. Therefore, the benefit from GDC-0941 could have been due to its modulation of Raf/MEK/ERK signaling. Here, we specifically test the importance of Akt signaling in MDS/MPN in KrasD12 and Nf1 mouse models using the allosteric inhibitor MK-2206. This compound binds to the interface of the PH and kinase domains of Akt1, Akt2, and Akt3, and does not inhibit any of 250 other kinases at 1 µM. MK-2206 induced substantial improvement in both KrasD12 and Nf1Δ/- mice. Mice treated with MK-2206 had pronounced reduction in leukocytosis, reticulocytosis and splenomegaly, increased hemoglobin concentration, and prolonged survival. MK-2206 had no hematologic effects in control WT mice, indicating some selectivity against aberrant hematopoiesis. Importantly, MK-2206 inhibited Akt but not Raf/MEK/ERK or Jak/STAT signaling. This demonstrates that canonical PI3K/Akt signaling plays an important role in Ras-driven MDS/MPN. Furthermore, combined inhibition of MEK and Akt with PD0325901+MK-2206 yielded a greater improvement in splenomegaly than either agent alone in both KrasD12 and Nf1Δ/- models. Akt has multiple effectors relevant to hematopoiesis and leukemia. Of these, mTOR is of particular interest for targeted cancer therapy. Therefore, we tested the response of KrasD12 mice to rapamycin, a partial inhibitor of mTOR with preferential activity against the mTORC1 complex. KrasD12 mice demonstrated variable responses to rapamycin, with approximately half undergoing a complete and durable hematologic response and the remainder having no response. Together, these studies further implicate PI3K/Akt signaling as a pathogenic effector downstream of Ras in MDS/MPN and support the idea that inhibitors targeting this pathway may have a role in treatment of JMML or CMML. Disclosures No relevant conflicts of interest to declare.

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Gnoni, Antonio, Antonella Licchetta, Riccardo Memeo, Antonella Argentiero, Antonio G. Solimando, Vito Longo, Sabina Delcuratolo et Oronzo Brunetti. « Role of BRAF in Hepatocellular Carcinoma : A Rationale for Future Targeted Cancer Therapies ». Medicina 55, n^o 12 (21 novembre 2019) : 754. http://dx.doi.org/10.3390/medicina55120754.

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The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC.

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Tamura, Ryota, et Masahiro Toda. « A Critical Overview of Targeted Therapies for Vestibular Schwannoma ». International Journal of Molecular Sciences 23, n^o 10 (13 mai 2022) : 5462. http://dx.doi.org/10.3390/ijms23105462.

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Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, a clinical trial using a VEGFR1/2 peptide vaccine was also conducted in patients with progressive NF2-associated schwannomas, which was the first immunotherapeutic approach for NF2 patients. Targeted therapies for the gene product of SH3PXD2A-HTRA1 fusion may be effective for sporadic VS. Several protein kinase inhibitors could be supportive to prevent tumor progression because merlin inhibits signaling by tyrosine receptor kinases and the activation of downstream pathways, including the Ras/Raf/MEK/ERK and PI3K/Akt/mTORC1 pathways. Tumor-microenvironment-targeted therapy may be supportive for the mainstays of management. The tumor-associated macrophage is the major component of immunosuppressive cells in schwannomas. Here, we present a critical overview of targeted therapies for VS. Multimodal therapy is required to manage patients with refractory VS.

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Patel, Meet, Adam Eckburg, Shahina Gantiwala, Zachary Hart, Joshua Dein, Katie Lam et Neelu Puri. « Resistance to Molecularly Targeted Therapies in Melanoma ». Cancers 13, n^o 5 (5 mars 2021) : 1115. http://dx.doi.org/10.3390/cancers13051115.

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Malignant melanoma is the most aggressive type of skin cancer with invasive growth patterns. In 2021, 106,110 patients are projected to be diagnosed with melanoma, out of which 7180 are expected to die. Traditional methods like surgery, radiation therapy, and chemotherapy are not effective in the treatment of metastatic and advanced melanoma. Recent approaches to treat melanoma have focused on biomarkers that play significant roles in cell growth, proliferation, migration, and survival. Several FDA-approved molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) have been developed against genetic biomarkers whose overexpression is implicated in tumorigenesis. The use of targeted therapies as an alternative or supplement to immunotherapy has revolutionized the management of metastatic melanoma. Although this treatment strategy is more efficacious and less toxic in comparison to traditional therapies, targeted therapies are less effective after prolonged treatment due to acquired resistance caused by mutations and activation of alternative mechanisms in melanoma tumors. Recent studies focus on understanding the mechanisms of acquired resistance to these current therapies. Further research is needed for the development of better approaches to improve prognosis in melanoma patients. In this article, various melanoma biomarkers including BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K are described, and their potential mechanisms for drug resistance are discussed.

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Afonso, Mariana, et Maria Alexandra Brito. « Therapeutic Options in Neuro-Oncology ». International Journal of Molecular Sciences 23, n^o 10 (11 mai 2022) : 5351. http://dx.doi.org/10.3390/ijms23105351.

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One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase receptors and their downstream pathways, such as the phosphatidylinositol 3-kinases (PI3K/AKT/mTOR) and mitogen-activated protein kinase pathways (MAPK). MAPK pathway inhibitors include farnesyl transferase inhibitors, Ras kinase inhibitors and mitogen-activated protein extracellular regulated kinase (MEK) inhibitors, while PI3K/AKT/mTOR pathway inhibitors are divided into pan-inhibitors, PI3K/mTOR dual inhibitors and AKT inhibitors. The relevance of the immune system in carcinogenesis has led to the development of immunotherapy, through vaccination, blocking of immune checkpoints, oncolytic viruses, and adoptive immunotherapy using chimeric antigen receptor T cells. In this article we provide a comprehensive review of the signaling pathways underlying malignant transformation, the therapies currently used in the treatment of malignant gliomas and further explore therapies under development, including several ongoing clinical trials.

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Czarnecka, Anna M., Ewa Bartnik, Michał Fiedorowicz et Piotr Rutkowski. « Targeted Therapy in Melanoma and Mechanisms of Resistance ». International Journal of Molecular Sciences 21, n^o 13 (27 juin 2020) : 4576. http://dx.doi.org/10.3390/ijms21134576.

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The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15–20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF).

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Rager, Taylor, Adam Eckburg, Meet Patel, Rong Qiu, Shahina Gantiwala, Katrina Dovalovsky, Kelly Fan et al. « Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies ». Cancers 14, n^o 15 (3 août 2022) : 3779. http://dx.doi.org/10.3390/cancers14153779.

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Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients.

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Breese, Erin Haag, Brian Turpin, Phillip Dexheimer, Benjamin Mizukawa, Laura Agresta, Arun Gurunathan, Thomas Pfeiffer et al. « Molecular signatures and responses to targeted therapies in over 300 relapsed and therapy-refractory young adult (AYA) and childhood cancers. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : 11514. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11514.

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11514 Background: Contemporary chemotherapy-based regimens provide cures for most pediatric & AYA cancers. However, for patients with relapsed/refractory malignancies, outcomes are poor & imply a distinct and aggressive biology. Identifying common themes in the molecular architecture & oncogenic mechanisms in these patients is a critical priority for drug development. We hypothesized that the molecular signature of cancers in these patients would be independent of histology. We also assessed the response to molecular alteration (MA)-targeted therapies. Methods: IRB-approved analysis of MAs in 306 relapsed/refractory pediatric & AYA malignancies (116 hematologic malignancies, 68 sarcomas, 46 neuroblastomas, 36 CNS, 14 liver, 9 renal, 17 other) was performed. DNA was analyzed for MAs (Foundation Medicine, Cambridge, MA; Univ of Washington, Seattle, WA); additional MAs were identified by cytogenetic & fluorescent in situ hybridization analyses. Results: Median age was 8 years (range birth - 44 yrs). MAs were identified in 90.1% of patients & included a median of 2 mutations (range 0-18) in 133 cancer-related genes. In contrast to genomic analyses of de novo malignancies in children, a high frequency of TP53 MAs was identified (20.4% of patients) and was associated with inferior survival. MAs were identified in targetable pathways including cell cycle regulation (32.6%), DNA repair (7.2%), epigenetic (28.6%), RAS/RAF/MEK (24%), tyrosine kinase (TK; 18.4%), PI3K/AKT/mTOR (11.8%), and NOTCH/WNT (8.9%). A higher number of MAs was associated with inferior survival. Patients with alterations in epigenetic & TK pathways also had inferior outcomes. MAs were frequently independent of histology & the spectrum of mutations was similar to adult cancers. Exceptional responses were observed with MA-based assignment of therapies (epigenetic, NTRK, RAS/RAF/MEK & ALK). Conclusions: Relapsed/refractory pediatric & AYA cancers have frequent MAs independent of histology. The spectrum of MAs is distinct from de novo disease & potentially reflects tumor evolution & resistance mechanisms. These findings support MA-guided approaches to new drug development paired with adult trials.

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Vachhani, Pankit, Prithviraj Bose, Mohamed Rahmani et Steven Grant. « Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML ». Physiological Genomics 46, n^o 13 (1 juillet 2014) : 448–56. http://dx.doi.org/10.1152/physiolgenomics.00173.2013.

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Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation, and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.

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Tamura, Ryota. « Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis ». International Journal of Molecular Sciences 22, n^o 11 (29 mai 2021) : 5850. http://dx.doi.org/10.3390/ijms22115850.

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Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.

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Lu, Yen-Jung, Kien Thiam Tan, Chun-Jung Chen, Ren-Shiang Jhou, Yi-Ting Yang, Chien-Hung Chen, Hua-Chien Chen, Shu-Jen Chen et David T. Chung. « Targeted gene sequencing panel for identifying actionable genomic alterations in Taiwanese lung cancer patients. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : e20522-e20522. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20522.

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e20522 Background: Lung cancer boasts an arsenal of targeted therapies directed at various molecular aberrations such as EGFR mutations and fusion genes. Simultaneous assessment for genetic alterations provides biomarkers to assist clinicians in their treatment selections. Methods: A total of 43 FFPE (formalin-fixed, paraffin-embedded) samples obtained from lung cancer patients in Taiwan were subjected to next-generation sequencing (NGS), using a compact panel encompassing 17 potentially actionable, lung cancer-associated genes. NGS was performed on the Ion Torrent PGM or Proton System with a targeted average depth of > 800x. Genomic alterations detected were categorized as single nucleotide variants (SNV) or chromosomal copy number alterations (CNA). Results: A total of 74 putatively actionable genomic alterations were detected across 38 patients (88.4%), which may predict sensitivity or resistance to established and/or therapies that are still in clinical development. 19 patients (44.2%) had tumors harboring activating EGFR mutations in the tyrosine kinase (TK) domain – L858R substitution or exon 19 deletion, which may suggest clinical benefit to first- and second-generation EGFR TK inhibitors (TKIs). Three patients (7.0%) whose tumor had acquired the EGFR T790M mutation were advised to switch to third-generation EGFR TKI. Possible resistance mechanisms to EGFR TKIs via increased copy number of EGFR (14.0%, n = 6) and MET (11.6%, n = 5) were observed. Deletion or loss of CDKN2A gene were detected in 14 patients (32.6%), which may confer sensitivity to CDK4/6 inhibitors. Inhibition of downstream effectors in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways were suggested for patients whose tumor harbored PIK3CA and/or KRAS oncogenic mutations. Conclusions: Next-generation sequencing using a compact panel of genes may be sufficient to identify biomarkers for targeted therapies selection for most lung cancer patients in Taiwan.

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Gibson, M. K., H. Mezzadra, L. Kleinberg, S. Jagannath, M. Brock, N. Abdallah, M. Rudek, D. Berman, A. Forastiere et S. Altiok. « Predicting and monitoring tumor response to epidermal growth factor receptor inhibitor gefitinib in patients with locally advanced esophageal adenocarcinoma ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 14112. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14112.

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14112 Background: This study aimed to validate an ex vivo chemosensitivity assay to measure the pharmacodynamic effect of gefitinib on esophageal adenocarcinoma (EAC) prior to treatment with pre-operative concomitant chemoradiotherapy (CRT). Methods: A 14 day run-in period with 250 mg/day of gefitinib preceded CRT. Endoscopic biopsies (D 0 and 14) in 4 patients with T2–3N0/1M0/1a EAC were analyzed by ex vivo chemosensitivity assay. Day 0 tissue was exposed to gefitinib ex vivo, then tumor was exposed to gefitinib for 14 days in vivo (ie in the patient). Phosphorylation of the EGFR, raf/MEK/ERK and PI3/AKT pathways was measured by Western blot. Profiles were compared for correlation between ex vivo and in vivo exposure, and patterns were correlated with response to CRT. The effects were also characterized by immunohistochemistry (IHC). EGFR, K-Ras, and PI3K mutations, serum concentrations of gefitinib and PTEN status were measured as potential confounders. Results: One patient with stage T3N1 died of unexplained hemorrhage during surgery. Three had clinical and path stages of: T3N1/T0N0, T3N0/T3N0, T3N1/T2N1. Gefitinib levels were constant, confirming exposure of target tissue to the drug. Ex vivo exposure yielded four distinct pathway patterns. The exact same patterns were seen after in vivo exposure. No mutations were identified in exons 18–21 of the EGFR, exons 2/3 of K-ras or exons 9/22 of PI3K. PTEN levels were similar in all tumors. PCNA expression correlated with raf/MEK/ERK pathway inhibition, but not with inhibition of EGFR activity. IHC correlated with Western blot for expression of EGFR, and phospho- and total ERK levels. No correlation was observed between gefitinib effect and pathologic response to CRT. Conclusions: This study used a novel ex vivo chemosensitivity assay to demonstrate the activity of gefitinib to inhibit target in tumor tissue obtained from patients with EAC. The exact correlation of pre- and post-treatment profiles suggests potential use in the pre-treatment setting to predict in vivo effects of targeted therapies. This approach may facilitate the further refinement of patient selection to maximize potential benefit while sparing patients unlikely to respond to a given agent. No significant financial relationships to disclose.

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Tsimberidou, Apostolia Maria, David S. Hong, Jennifer J. Wheler, Gerald Steven Falchook, Aung Naing, Siqing Fu, Sarina Anne Piha-Paul et al. « Precision medicine : Clinical outcomes including long-term survival according to the pathway targeted and treatment period–The IMPACT study. » Journal of Clinical Oncology 36, n^o 18_suppl (20 juin 2018) : LBA2553. http://dx.doi.org/10.1200/jco.2018.36.18_suppl.lba2553.

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LBA2553 Background: We evaluated the impact of pathway targeted and long-term follow-up of patients (pts) with refractory cancers referred to phase I trials. Methods: Pts referred to our program (2007-2013) had CLIA molecular testing. Pts treated with matched targeted therapy (MTT) vs. non-matched therapy (NMT) were analyzed. Results: Of 3,743 pts who had testing, 1,307 had ≥1 alteration and received therapy (MTT 711, NMT 596): med. age 57 yrs, range 16-86; 39% men; med. no. of prior therapies 4, range 0-16. The most common tumors were gastrointestinal 24.2%, gynecologic 19.4%, breast 13.5%, melanoma 11.9%, and lung 8.7%. Targeting MEK/RAF and RET pathways correlated with higher rates of CR/PR/SD≥6 months (mos), PFS and OS compared to others (all P < .001) (Table). Plateau was noted in OS (start, 38 mos): 74 of 711 (10.4%) in the MTT (max 10.7+ yrs) vs. 24 of 596 (4%) in the NMT (max 6 yrs) group were alive (p < .0001). In the MTT group, factors predicting longer PFS were non-PI3K pathway MTT (p < .001), no liver metastases (p < .001), PS < 2 (p = .006), normal LDH (p < .001) and albumin (p = .01) levels, and non-single agent therapy (p = .02). Factors predicting longer OS were non-PI3K pathway MTT (p < .001), no liver metastases (p < .001), PS < 2 (p < .001), normal LDH (p < .001) and albumin (p = .001) levels, and normal PLT counts (p = .03). Conclusions: Outcomes were superior in pts matched to RET and MEK/RAF inhibitors. Factors predicting longer PFS and OS were identified. In the MTT group, 10.4% of patients had OS ≥ 38 mos, the plateau starting point. Clinical trial information: NCT00851032. [Table: see text]

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Williams, Gareth, Alexander Llewelyn, Robert Thatcher, Keeda-Marie Hardisty et Marco Loddo. « Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma ». PLOS ONE 17, n^o 3 (24 mars 2022) : e0245817. http://dx.doi.org/10.1371/journal.pone.0245817.

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The standard treatment for glioblastoma involves a combination of surgery, radiation and chemotherapy but have limited impact on survival. The exponential increase in targeted agents directed at pivotal oncogenic pathways now provide new therapeutic opportunities for this tumour type. However, lack of comprehensive precision oncology testing at diagnosis means such therapeutic opportunities are potentially overlooked. To investigate the role of semiconductor sequencing for detection of predictive biomarkers in routine glioblastoma samples we have undertaken analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture actionable genomic variants distributed across 505 genes. Analysis was performed across a cohort of 55 glioblastoma patients. Analysis of trending data has revealed a complex and rich actionable mutational landscape in which 166 actionable mutations were detected across 36 genes linked to 17 off label targeted therapy protocols and 111 clinical trials. The majority of patients harboured three or more actionable mutations affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signalling pathways, DNA-damage repair pathways and cell cycle checkpoints. Linkage with immunotherapy and PARP inhibitors was identified in 44% of glioblastoma patients as a consequence of alterations in DNA-damage repair genes. Taken together our data indicates that precision oncology testing utilising semiconductor sequencing can be used to identify a broad therapeutic armamentarium of targeted therapies and immunotherapies that can be potentially employed for the improved clinical management of glioblastoma patients.

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Nobre, Liana, Adrian Levine, Scott Milos, Monique Johnson, Ben Laxer, Scott Ryall, Julie Bennett et al. « BIOM-09. GUIDING PRECISION THERAPEUTICS THROUGH INTERROGATING ONCOGENIC PATHWAY ACTIVATION ». Neuro-Oncology 24, Supplement_7 (1 novembre 2022) : vii5—vii6. http://dx.doi.org/10.1093/neuonc/noac209.019.

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Abstract The deregulation of canonical oncogenic pathways are largely responsible for driving pediatric cancers and can be targeted for therapeutics. Currently, we interrogate these pathways clinically by looking for gene mutations, but these are not found in all cases, and in others multiple genes are. We hypothesized that assessing transcriptomic and proteomic-based pathway activation will allow a better understanding of the most active oncogenic pathways and help guide therapy. To do this, we developed and validated a nanostring based assay that interrogates 4 key actionable pathways (MAPK, PI3K-AKT-mTOR, JAK-STAT, and NFkB) including RNA, protein and phosphoprotein expression. The assay was clinically validated using isogenic cell lines and a cohort of 40 gliomas with previous RNAseq. We then interrogated over 400 tumor samples, including 15 ependymomas, 11 medulloblastomas, 250 low grade gliomas (LGG), 145 high grade gliomas and 10 control normal brain specimens. Interestingly, although pediatric LGG exhibited higher MAPK activation than control tissue and other tumor types, a subset of these tumors have increased activity in PI3K , JAK and NFKB pathways. Furthermore, high PI3K activation score was correlated with worse PFS in a subset of pediatric LGGs that required adjuvant chemotherapy (p=0.018). To further explore the therapeutic implication of the assay, we analyzed a cohort of patients treated with MEK inhibitors (n=20). Strikingly, on top of universal RAS/MAPK activation, crosstalk between additional activated pathways such as PI3K and JAK-STAT may contribute to lack of response. In particular, pre-treatment and post-progression PLGG who failed therapy, revealed mild reduction in MAPK signature accompanied by increased PI3K phospho-proteins (p-S6/p-4EBP1,p-AKT)(p< 0.01). We conclude that assessing oncogenic pathway activation can add to DNA sequencing to predict different outcome and response to targeted therapies in childhood brain tumors. This can inform future therapeutic strategies including the identification of potential responders and combination strategies for non-responders.

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Teo, M., H. T. Huynh, S. W. Hee, Y. P. Phoon, R. Quek, P. Wang et H. C. Toh. « FOXO3a predicts for survival and its phosphorylated form is downregulated following mTOR or MEK inhibitor therapy in Hepatocellular Carcinoma ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 4538. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4538.

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4538 Background: Hepatocellular carcinoma (HCC) is an aggressive cancer endemic in Asia with few effective treatments. We hypothesize that FOXO3a may be a potential prognostic marker in HCC and analyze the effects of targeted therapy acting on the PI3K/AKT pathway, of which FOXO3a is downstream. PI3K activates serine/threonine protein kinase AKT, causing FOXO3a phosphorylation and its nuclear translocation, promoting apoptosis. Tumor suppressor, promyelocytic leukemia (PML), inactivates nuclear phosphorylated AKT (pAKT). mTOR, also of the P13K/AKT pathway, is dysregulated in many cancers. PI3K is an effector of RAS, which controls downstream mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) pathway. AZD6244 is a selective inhibitor of MEK1/2. RAD001 (Everolimus) specifically inhibits mTOR. Avastin (bevacizumab) is an anti-angiogenic agent. These therapies have shown clinical efficacy in various cancers, including preliminary results with either RAD001 or avastin treatment in HCC. Method: We analyzed FOXO3a status in 91 stage I and II HCC patients using relative real-time PCR and immunoblotting analysis. Using a primary human HCC xenograft SCID mouse model, we examined tumor efficacy and molecular effects of AZD6244, RAD001 and Avastin treatment. Results: The median survival of the high FOXO3a-expressing group (2-fold increased expression vs normal, >2.0, n=16) was 27 months versus 95 months for the low expressing group (2-fold decreased expression vs normal, <0.5, n=58) (p=0.037). Pearson correlation analysis indicated a positive correlation between FOXO3a and PML (n=46, correlation=0.533, p<0.001). Immunoblotting results for 8 random HCC samples reveal increased levels of pFOXO3a (Ser253) in all tumor tissue compared to adjacent normal. Treatment of HCC xenograft mice with AZD6244 or RAD001 caused significant tumor shrinkage and reduced levels of pAKT (Ser308) and pFOXO3a (Ser318). Avastin had cytostatic effects and unchanged levels of pFOXO3a (Ser318). Conclusion: FOXO3a predicts for overall survival in HCC. A positive correlation is established between FOXO3a and PML. AZD6244 and RAD001 can induce tumor regression via the AKT-FOXO3a pathway in HCC xenografts. No significant financial relationships to disclose.

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Yaktapour, Niuscha, Christine Dierks, Dietmar Pfeifer, Hassan Jumaa, Hendrik Veelken, Tilman Brummer et Katja Zirlik. « Combination Of Kinase Inhibitors Overcomes B-Raf Inhibitor-Induced Paradoxical ERK Activation In CLL Cells In Vitro – Potential Implications For CLL Treatment ». Blood 122, n^o 21 (15 novembre 2013) : 4121. http://dx.doi.org/10.1182/blood.v122.21.4121.4121.

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Abstract Chronic lymphocytic leukemia (CLL) remains incurable with current state of the art therapy creating the need for novel therapeutic concepts. Kinase inhibitors represent a promising strategy in the treatment of various malignancies including CLL. However, based on the recent experience with other targeted therapy compounds used as single agents, it appears important to identify additional targets and to evaluate therapeutic combinations targeting two or more critical signaling hubs in CLL cells. This strategy is likely to counteract the development of drug resistance more efficiently. We and others recently showed that the Raf/MEK/ERK pathway plays a critical role for the in vitro survival of CLL cells and demonstrated that drugs such as sorafenib targeting all Raf-isoforms and other kinases, induce apoptosis. Here, we provide a detailed analysis of various B-Raf inhibitors, including sorafenib, PLX4720 (vemurafenib tool compound) and dabrafenib on apoptotic pathways in primary human CLL cells and their impact on CLL cell survival alone or in combination with MEK (U0126), dual phosphoinositide-3 kinase/mTOR inhibitor (BEZ235), and IGF1R inhibitors (AG1024, Picropodophyllin (PPP)). 10µM sorafenib, a concentration comparable to plasma levels of this drug in patients, strongly induced apoptosis in CLL cells, while the more specific B-Raf inhibitor PLX4720 did not affect viability. This discrepant finding may be attributed to PLX4720’s well-described paradoxical ERK activation reported in various solid tumor types lacking BRAF mutations and containing increased Ras-GTP levels. Indeed, only sorafenib reduced ERK phosphorylation in CLL cells, while PLX4720 treatment even enhanced ERK activation. Interestingly, not only the B-Raf inhibitors PLX4720 or dabrafenib, but also lower doses (1-5µM) of sorafenib induced paradoxical ERK activation. Most likely, at these concentrations drug-bound Raf molecules act as potent allosteric activators on drug-free Raf monomers, thereby leading to an increase in ERK pathway activity. Importantly, paradoxical ERK activation coincided with enhanced viability. In line with findings in melanoma cells, BRAF (V600E) mutated CLL cells showed no paradoxical ERK activation and were effectively killed by the respective compounds. To identify inhibitor combinations reducing the in vitro survival of BRAF wild-type CLL isolates, we combined the B-Raf inhibitors with the MEK inhibitor U0126 or the dual PI3K/mTOR inhibitor BEZ235 observing reduced ERK phosphorylation and significantly enhanced rates of cell death (p<0.0009 for U0126; p<0.01 for BEZ235). This indicates that the additional MEK or PI3K inhibition counteracts paradoxical ERK activation in vitro and may overcome the resistance to apoptosis induction mediated by paradoxical ERK activation. Likewise, we tested combinatory effects of IGF1R inhibitors (AG1024, PPP) with suboptimal sorafenib doses and observed a significantly enhanced cell death for the combinations AG1024 and sorafenib (p<0,0001) as well as PPP and sorafenib (p<0,0001). In conclusion, this is the first description of a paradoxical ERK activation by Raf inhibitors in CLL cells with unmutated BRAF. Our observation of paradoxical ERK activation after treatment with suboptimal sorafenib doses may be of clinical importance since sorafenib is currently investigated in clinical trials in several malignancies including CLL. Our findings imply that Sorafenib plasma concentrations should be monitored when used for the treatment of CLL since lower plasma levels might promote paradoxical ERK activation and CLL progression. Furthermore, our results show the potential of therapies combining kinase inhibitors: additional MEK or PI3K inhibition or the concomitant inhibition of both pathways by IGF1R inhibitors may overcome paradoxical ERK activation. Furthermore, given our recent observation that the IGF1R is overexpressed in CLL cells, its inhibition by IGF1R kinase inhibitors might be advantageous over the single inhibition of MAPK or PI3K pathway components. Disclosures: No relevant conflicts of interest to declare.

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Lilleberg, Stan L., Jeffrey Durocher, Jill Hempel, Carrie Wasserburger, Manika Koul, John Troy et Mike L. Nickerson. « In-Depth Mutation Scanning of Signaling Pathway Genes Involved in the Development and Targeted Treatment of Hematopoietic Malignancies. » Blood 106, n^o 11 (16 novembre 2005) : 4399. http://dx.doi.org/10.1182/blood.v106.11.4399.4399.

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Abstract The Raf/MEK/ERK, Wnt/beta-catenin, JAK/STAT and PI3K/Akt signal transduction pathways have key roles in the regulation of cell cycle progression and apoptosis, and are current focal points of therapeutic development and intervention strategies for hematopoietic neoplasias. These pathways have several regulatory components that keep proliferative and anti-apoptotic mechanisms in check, but which can also drive neoplastic processes when their functions are altered by genetic and epigenetic events. Links between critical pathways are also being established and, although only partially understood, may provide important clues for the development of more efficacious therapies that target multiple pathways. Although mutations in several pathway-associated genes known to contribute to the malignant phenotype have been discovered, the mutation status of the pathway as a whole in a particular blood cancer type remains to be determined. In this study, we applied novel mutation detection technologies (DHPLC, Surveyor Nuclease, and fluorescent DNA sequencing) in a combinatorial fashion to achieve high throughput, accuracy, and sensitivity for a comprehensive screening of signal transduction pathway genes. Key targets for the analysis included genes encoding receptor tyrosine kinases, cytoplasmic kinases, GTPases, transcription factors and tumor suppressors, with emphasis on Raf/MEK/ERK and PI3K/AKT pathways. We present both somatic alterations and inherited polymorphisms (SNPs) in these genes from the analyses of AML and CML sample sets. Functional analyses will confirm the causative nature of these genetic variants and their contributions to tumorigenesis. Other groups have focused on gene families for analysis of somatic mutations in tumors, such as kinases and phosphatases. This study takes a signaling pathway approach to group gene targets for analysis. We believe that pathway-based mutation analysis strategies offer significant potential to enhance understanding of cancer initiation, disease progression, response to therapy, and mechanisms of drug resistance.

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Flandrin-Gresta, Pascale, Lydia Campos, Emmanuelle Tavernier-Tardy, Amelie Duval, Nathalie Nadal et Denis Guyotat. « Activation of Multiple Signal Transduction Pathways as a Prognostic Marker in Acute Myelogenous Leukemia. » Blood 110, n^o 11 (16 novembre 2007) : 2395. http://dx.doi.org/10.1182/blood.v110.11.2395.2395.

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Abstract Deregulation of signal transduction pathways (STPs) including JAK/STAT, RAS/Raf/MEK/ERK and PI3K/AKT may promote leukemogenesis by conferring cells proliferation and survival advantages in acute myelogenous leukemia (AML). The activation of these pathways had an adverse prognosis in AML and development of targeted therapies seems to be promising. Heat-shock proteins (HSP) are involved in the conformational maturation of a number of signaling proteins, and HSPs expression in AML is associated with other adverse prognostic factors (Bcl2, MRP). The aim of this work was to study STPs expression in AML, and there correlation to other adverse prognostic factors and complete remission rate. Sixty five patients with primary AML were analyzed by flow cytometry for constitutive ERK, PI3K and AKT activation, HSP90, Bcl2 and P170 expression. FAB subtypes were M0=3, M1=19, M2=16, M4=10, M5=16, M6=1. All patients received an induction treatment, 44 patients reached complete remission. Cytogenetics was available in 63 cases (Intermediate = 36, favorable = 3, unfavorable= 24). We performed a 3 color flow cytometry protocol using CD45 and CD34 to identify blast cells, and used a third antibody to the following transduction proteins (ERK, pERK, AKT, pAKT, PI3K) or intracytoplasmic proteins (Bcl2, HSP90, p170). Spontaneous growth of leukemic progenitor cells (CFU-L) was investigated in 44 samples. In AML, activated proteins were found in CD34+ cells. ERK and PI3K/AKT were frequently co-activated. Flow cytometry results showed that levels of STPs were significantly higher (p<0,05) in patients who did not reach complete remission, with a shorter survival: PI3K (12% of positive cells for CR patients vs 68% for non CR patients), ERK (17% vs 69%), pERK (15% vs 77%), AKT (24% vs 76%) and pAKT (10% vs 79%). All patients who reached complete remission had a percentage of positive cells < 20% (except 2 cases for AKT). Interestingly, the levels did not differ significantly according to cytogenetics, and were only marginally higher in patients with high WBC, which suggests an independent prognostic value. By contrast, we found a good correlation between activation of signaling pathways and HSP90, Bcl2 and p170 expression (p<0,05). We observed a spontaneous growth in 30 cases (defined by more than 10 colonies/105cells), with a good correlation with HSP90, Bcl2, p170 and CD34 expression. By contrast, there was no correlation between spontaneous growth and activation of STPs, suggesting that spontaneous growth of leukemic cells which is also a prognostic factor is not directly related to activation of STPs. These results indicate that the activation of multiple STPs is common in AML and is associated with poor prognosis, and that flow cytometry technique can be used for rapid detection of AML patients who are resistant to conventional chemotherapy. This is of particular interest because of development of targeted therapies for signaling transduction pathways, chaperones and anti-apoptotic proteins.

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Altunel, Erdem, Jason Somarelli, So Young Kim, Wayne Glover, Gabrielle Rupprecht et Shiaowen David Hsu. « A precision medicine strategy to identify the FGFR pathway as a novel target in colorectal cancer liver metastasis. » Journal of Clinical Oncology 36, n^o 4_suppl (1 février 2018) : 660. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.660.

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660 Background: Colorectal cancer liver metastasis (CRCLM) continues to be a major health problem and despite extensive efforts to develop new drugs, median survival remains at a mere 30 months. The purpose of our study is 1. Develop a precision medicine strategy for patients with CRCLM and 2. Discover novel pathways and treatments to improve outcomes. Methods: In order to develop a precision medicine strategy, 6 matched patient derived xenografts (PDX) and cell lines were established from patients undergoing resection of their CRCLM. A high-throughput drug screen containing over 100 FDA approved drugs was first used in vitro on 3 cell lines to identify therapeutic targets. The top therapeutic targets were validated in vivo. RNA seq was then performed to identify potential predictive markers of response. Results: Our high-throughput drug screen performed on 3 early passage CRC cell lines (CRC057, CRC119 and CRC240) identified ponatinib, a multi TKI, as the only agent to inhibit all 3 cell lines. Subsequent growth inhibition analysis identified the fibroblast growth factor receptor (FGFR) as the main target of ponatinib. In vitro findings were confirmed in vivo in matched PDXs. Western blot analysis post treatment showed evidence of decreased phospho-FGFRs. Further analysis of the main downstream signaling pathways of FGFR (RAS/PI3K/AKT, RAS/MEK/ERK and STAT) demonstrated that the STAT pathway was effectively targeted in all 3 cell lines. In contrast, the ERK pathway was targeted in CRC240 and CRC057 while the p-AKT was targeted in CRC119. Finally, RNAseq revealed different isoforms and mutations in these samples. Conclusions: We have developed a precision medicine strategy for patients with CRCLM using matched cell lines and PDXs coupled with high throughput drug screens and genomic analysis to identify novel targets and specifically identified the FGFR/STAT axis as a therapeutic target. Furthermore, co-targeting FGFR and its downstream pathways may provide synergy and lead to combinatorial therapies that can improve patient outcomes. Finally, RNAseq data can be used to develop predictive markers of therapy.

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McQueen, Teresa, Marina Konopleva et Michael Andreeff. « Activity of Targeted Molecular Therapeutics Against Primary AML Cells : Putative Role of the Bone Marrow Microenvironment. » Blood 106, n^o 11 (16 novembre 2005) : 2304. http://dx.doi.org/10.1182/blood.v106.11.2304.2304.

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Abstract In hematological malignancies, there are reciprocal interactions between leukemic cells and cells of the bone marrow (BM) microenvironment such as mesenchymal stem cells (MSC). It is speculated that specific BM niches may provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. In this study, we compared anti-leukemia effects of Ara-C and various signal transduction and apoptosis inhibitors in a co-culture system of primary AML and human bone marrow-derived MSC. AML blasts from 11 primary AML samples with high (>70%) blast count were co-cultured with MSC for 24 hours, after which they were exposed to the indicated concentrations of inhibitors for 48–96 hrs. Concentrations were selected on the basis of preliminary cell line studies which determined efficient inhibition of drug targets. Induction of apoptosis was analyzed by Annexin V flow cytometry after gating on the CD90 APC(−) (non-MSC) population. MSC protected leukemic blasts from spontaneous apoptosis in all 11 samples studied (mean annexinV positivity, 49.5±7.2% vs 25.3±4.8%, p<0.001) and from Ara-C-induced cytotoxicity in 6 out of 11 samples (p=0.02). No difference in the degree of protection was noted when MSC from older vs. younger donors were used (not shown). Co-culture of leukemic cells with MSC resulted in significant (p<0.03) suppression of inhibitor-induced apoptosis for all agents tested (Table 1), however PI3K/AKT inhibitors seemed to overcome MSC-mediated resistance. In addition, specific inhibitors of Bcl-2 and MDM2 induced apoptosis not only in suspension, but also in the MSC co-culture system, while Raf-1/MEK inhibitors were less effective. The AKT inhibitor A443654 caused apoptosis induction not only in leukemic cells, but also in MSC, which likely accounted for its high efficacy in stromal co-cultures (53±6% annexin V+). In a different study (Tabe et al, ASH 2005), we report that interactions of leukemic and BM stromal cells result in the activation of PI3K/ILK/AKT signaling in both, leukemic and stromal cells. We therefore propose that disruption of these interactions by specific PI3K/AKT inhibitors represents a novel therapeutic approach to eradicate leukemia in the BM microenvironment via direct effects on leukemic cells and by targeting activated BM stromal cells. Furthermore, Bcl-2 and MDM2 inhibitors appear to retain their efficacy in stroma-cocultured AML cells, while the efficacy of chemotherapy and Raf/MEK inhibitors in these conditions may be reduced. Further studies are aimed at the elucidation of the role of the BM microenvironment and its ability to activate specific signaling pathways in the pathogenesis of leukemias and on efforts to disrupt the MSC/leukemia interaction (Zeng et al, ASH 2005). Focus on this stroma-leukemia-stroma crosstalk may result in the development of strategies that enhance the efficacy of therapies in hematological malignancies and prevent the acquisition of a chemoresistant phenotype. Table 1. Leukemia Cell Apoptosis in a MSC/AML Co-Culture System Target Bcl-2/XL MDM2 PI3K AKT Raf-1 MEK Apoptosis was determined as percentage of Annexin V(+)CD90(−) cells, and calculated by the formula: % specific apoptosis = (test − control) x 100 / (100 − control). Compound, concentration Ara-C, 1 μM ABT-737, 0.1 μM Nutlin-3A, 2.5 μM LY294002, 10 μM A443654, 1 μM BAY43-9006, 2.5 μM CI1040, 3 μM AML 28±7 69±7 45±7 53.8±13.3 75±7 35±11 27±11 AML + MSC 16±4 38±6 28±6 31.2±6.9 53±6 18±8 15±5

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Salinas, Ryan, Daniel Zhang, Fadi Jacob, Phuong Nguyen, Saad Sheikh, Stefan Prokop, Jay Dorsey et al. « TMOD-25. GLIOBLASTOMA ORGANOIDS : A MODEL SYSTEM FOR PATIENT-SPECIFIC THERAPEUTIC TESTING ». Neuro-Oncology 21, Supplement_6 (novembre 2019) : vi268. http://dx.doi.org/10.1093/neuonc/noz175.1124.

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Abstract Glioblastoma treatment options remain limited due to its aggressive and invasive nature. It is increasingly appreciated that molecular heterogeneity between tumors and within tumors likely contributes to the lack of therapeutic advances. To maintain the inherent heterogeneity of glioblastoma, we employed a novel method to rapidly culture glioblastoma organoids (GBOs) directly from neurosurgical resection. GBOs are routinely generated around two weeks following initial resection. Comprehensive histologic and sequencing analyses demonstrated similarity to primary tumors. Leveraging clinical molecular and sequencing data, selected GBOs were treated with radiation/temozolamide and targeted inhibitor therapies. The effect on proliferation was measured by the percentage of KI67+ cells and gene set enrichment (GSEA) analysis was performed to compare the pre-treated expression signature amongst responsive and non-responsive tumors. Treatment of organoids with radiation/temozolamide led to a decrease in the percentage of KI67+ cells in four of eight patient-derived organoid lines with some evidence of correlative radiographic response Gene sets associated with radiation response and TNF signaling were enriched in radiation/temozolamide sensitive GBOs. GBO response to EGFR inhibition via gefitinib treatment was specific to EGFR altered tumors, whose expression also enriched for EGF signaling pathway expression. Two GBOs had downstream NF1 mutations that responded to the MEK inhibitor trametinib. On GSEA, gene expression of NF1 mutated GBOs enriched for RAS signaling. One GBO line was found to have a PI3K mutation and responded dramatically to mTOR inhibition via everolimus. Dichotomous efficacy of MEK and mTOR inhibition was also noted by tumor-specific changes in GBO diameter following treatment. This novel culturing method of GBOs maintains intertumoral and intratumoral heterogeneity and allows for therapeutic testing within two weeks of neurosurgical resection. As clinical sequencing because increasingly prevalent, GBOs may become a valuable tool to functionally test mutation-specific treatment strategies in a patient-specific manner within a clinically relevant time frame.

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Schade, Andrew E., Anna M. Jankowska, Hadrian Szpurka et Jaroslaw P. Maciejewski. « Pharmacologic Inhibition of Src Family Kinases Differentially Affects T Cell Cytokine Production and Proliferation : Implications for Novel Immunomodulatory Therapies. » Blood 110, n^o 11 (16 novembre 2007) : 1349. http://dx.doi.org/10.1182/blood.v110.11.1349.1349.

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Abstract It is well-recognized that the T cell receptor (TCR) signaling pathway, catalyzed by the Src family kinase (SFK) Lck, is the essential first step in T cell immune responses. The long-held goal of specifically targeting SFK activity for immunomodulatory therapy is becoming more of a reality as SFK inhibitors are entering into clinical use. In particular, dasatinib is an oral small molecule inhibitor of Abl and SFK, including Lck. Given the central importance of Lck in transmitting signals from the TCR signaling complex, and the potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent could provide a novel route of immunomodulation via targeted inhibition of antigen-induced signaling, particularly in combination with currently available immunomodulatory agents. Using intracellular phospho-flow cytometry and western blotting, we show that low nanomolar concentrations of dasatinib potently inhibit TCR induced global protein tyrosine phosphoryation, including the key signaling elements CD3, ZAP-70, LAT, and PLC. In addition, the second messenger pathway Ras/Raf/MEK/ERK is potently blocked, whereas the PI3K-AKT pathway is minimally affected. Furthermore, induction of many pro-inflammatory cytokines, including TNF-α, IFN-γ, IL-2, GM-CSF, IL-17, IP-10, RANTES, and IL-6 (measured by cytokine antibody array) was significantly inhibited when the TCR was triggered in the presence of dasatinib. T cell proliferation, assessed by flow cytometric CFSE dilution analysis, was inhibited in a dose-dependent manner with dasatinib, showing complete inhibtion at 10 nM. Cell cycle analysis based on DNA content by PI staining revealed that dasatinib-treated T cells failed to enter the cell cycle. Considering that the PI3K-AKT pathway was only minimally affected by dasatinib, we examined the ability to achieve enhanced inhibition by using sub-optimal doses of dasatinib and rapamycin that individually produce mild-moderate inhibition of proliferation (20% and 40% inhibition, respectively). When dasatinib and rapamycin are combined at these lower doses, there was a consistently enhanced inhibitory effect on T cell proliferation (80–95% inhibition). Concurrent CD28 stimulation failed to overcome the inhibitory effects of SFK inhibition when the inhibitor was present throughout the stimulation. Interestingly, when SFK inhibition was delayed for at least 24 hours after the initiation of T cell activation with concurrent CD28 stimulation, we observed a divergent effect with regard to cytokine production and proliferation. Pro-inflammatory cytokine production was significantly decreased even if SFK activity was inhibited 48 hours after stimulating T cells, suggesting that ongoing TCR-dependent SFK activity is essential for cytokine production. However, late inhibition of SFK activity with dasatinib increased proliferation, with greater numbers of T cells achieving more rounds of cell division. Thus, while necessary for cytokine production, once the cells have entered the cell cycle, SFK activity regulates negative feedback in CD28-mediated proliferation. In conclusion, targeted inhibition of SFK activity is a promising approach for novel immunomodulatory therapy, particularly in combination with other signaling pathway inhibitors, but timing of SFK inhibition in relation to T cell activation could have an important impact on the immunomodulatory effect.

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Majumder, Muntasir M., David Tamborero, Pekka Anttila, Raija Silvennoinen, Samuli Eldfors, Ashwini Kumar, Juha Lievonen et al. « DNA Damage Repair Pathway Alterations in Multiple Myeloma Predict Poor Prognosis, but Correlate with Sensitivity to IGF1R-PI3K-mTOR and HDAC Inhibitors ». Blood 128, n^o 22 (2 décembre 2016) : 198. http://dx.doi.org/10.1182/blood.v128.22.198.198.

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Abstract Introduction Although several novel drugs have recently been approved or are in development for multiple myeloma (MM), there are few molecular indicators to guide treatment selection. In addition, the impact of recurrent myeloma alterations on drug response is often unclear. To address these limitations and elucidate genotype to phenotype relationships in myeloma, we comprehensively analyzed 100 MM samples and compared genomic, transcriptomic, and cytogenetic information to ex vivo drug response profiles and clinical outcome of individual MM patients. Our results reveal novel insights on i) drug response and resistance mechanisms, ii) biomarkers for drug response, and iii) potential treatment combinations to overcome drug resistance. Methods Bone marrow aspirates were collected from MM patients (n=100; newly diagnosed n=34; relapsed/refractory n=66) and healthy individuals (n=14). CD138+ plasma cells were enriched from the mononuclear cell fraction by immunomagnetic bead selection. Cells were screened against 142 oncology drugs tested in a 10,000-fold concentration range and 12 different drug combinations Somatic alterations were identified by exome sequencing of DNA from CD138+ cells and skin biopsies from each patient (n=85). RNA sequencing derived read counts from CD138+ cells of MM samples (n=67) were used for differential gene expression. Karyotype was determined by fluorescence in situ hybridization. Results For most drugs tested, no significant difference in response was observed between samples from newly diagnosed and relapsed refractory patients except for signal transduction inhibitors targeting IGF1R-PI3K-mTOR, MAPK and HSP90. A positive correlation was observed between mutational burden and sensitivity to targeted therapies. The median number of somatic alterations was 118 in sensitive compared to 50 in resistant samples. 14% of the samples exhibited a multidrug resistant phenotype and were resistant to proteasome inhibitors, immunomodulatory drugs and glucocorticoids. 30% of the resistant samples were from del(17p) patients. In addition, gene expression analysis revealed elevated expression of cell adhesion and integrin signaling molecules including ITGB3, ITGA2B, VCL, TLN1, MMP8, MMP9, plus ABCC3, which encodes a transporter protein shown to be associated with multidrug resistance. A combination of the protein kinase C inhibitor bryostatin-1 and pan-BCL2 inhibitor navitoclax was highly effective against the resistant samples. 26% of the patient samples harbored mutations in genes involved in DNA damage repair signaling, namely TP53, TP73, ATM and BAX, in a mutually exclusive pattern. In addition, patients with these mutations had a high relapse rate and poor overall survival (HR=7.2,95%CI 3.2-16.08). Interestingly, CD138+ cells from these patients showed activation of IGF1R-PI3K-mTOR signaling and were highly susceptible to inhibitors targeting this signaling axis. These samples were also highly sensitive to HDAC inhibitors. While no strong correlation between RAS pathway mutations (NRAS, KRAS, NF1, BRAF) and MEK inhibitor sensitivity was observed, samples with clonal RAS mutations tended to be more sensitive to MEK inhibitors compared to samples with subclonal mutations. Summary Our results suggest that drug resistance in myeloma may occur either via accumulation of somatic alterations or via cell adhesion mediated cytoprotection. Driver alterations in DNA damage signaling pathways were found to contribute to poor prognosis, but samples with these mutations showed enhanced sensitivity to IGF1R-PI3K-mTOR and HDAC inhibitors. Using genomic and transcriptomic data we identified molecular events that may shape the drug response landscape and found drug combinations that can overcome resistance mechanisms. Our results demonstrate that molecular information and ex vivo drug profiling may be useful to develop tailored treatment strategies and guide treatment decision, especially for relapsed/refractory myeloma patients. Disclosures Silvennoinen: Sanofi: Honoraria, Other: Lecture fee; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fee; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Heckman:Pfizer: Research Funding; Celgene: Research Funding.

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Allegretti, Matteo, Maria Rosaria Ricciardi, Martina Vincenzi, Roberto Licchetta, Simone Mirabilii, Sergio Amadori, Robin Foà et Agostino Tafuri. « The Phosphatidylinositol-3-Kinase Inhibitor BKM120 Impairs Proliferation and Induces Pro-Apoptotic Effects In Acute Myeloid Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 4222. http://dx.doi.org/10.1182/blood.v122.21.4222.4222.

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Abstract Acute myeloid leukemia (AML) has been characterized by a growing number of recurrent genetic alterations, frequently causing the constitutive activation of signal transduction pathways, which result in enhanced blast proliferation and prolonged survival. Despite the increased understanding of AML biology, prognosis of these patients remains, generally, severe. Therefore, novel therapies targeted on aberrant signaling are now under evaluation. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway plays a pivotal role in the control of cell growth, proliferation and apoptosis of AML, and is often found constitutively activated. Currently, several inhibitors of this pathway, especially those inhibiting the activity of mTOR, have been investigated showing a limited efficacy due to the reactivation of upstream nodes. Since a novel PI3K inhibitor, BKM120, has been evaluated with encouraging results on solid tumors and lymphoid malignancies, we aimed in this study to investigate the pre-clinical activity of BKM120 on cell lines and primary AML samples. BKM120, kindly provided by Novartis, was tested on myeloid leukemia cell models - U937, MOLM13, OCIAML3 and KG1 - and on 4 primary AML samples at concentrations ranging from 0.5 to 5µM. Cell cycle changes and apoptosis induction were analyzed using the Acridine-Orange technique (AO) and the Annexin V (AnnV) binding assay. Intracellular signaling modulations induced by BKM120 were evaluated at different times (3h and 24h) by Western blot analysis. BKM120 exhibited dose- and time-dependent anti-proliferative and pro-apoptotic effects on the all analyzed leukemia cell models, although with different sensitivity (IC50s of 1.6, 2.4, 2.7 and 3.2μM for the U937, MOLM13, OCIAML3 and KG1 cell lines, respectively). On the most sensitive cell line U937, BKM120 in vitro exposure resulted, at 24h, in a significant cell growth reduction of 48.6% (p=0.006) and 73.9% (p=0.006), at 1 and 2µM, respectively. After 72h of treatment, AnnV positive cells significantly increased from 7.4% ± 0.03 (vehicle) to 43.5% ± 0.08 (p<0.001) and 89.4% ± 0.05 (p<0.001), at 1 and 2μM BKM120, respectively. On the less sensitive cell line KG1, the percentage of apoptotic cells reached 49.6% ± 0.1 and 56.6% ± 0.2 at 2 and 5μM BKM120, respectively. Since our previous data (Ricciardi MR et al., JMM, 2012) have been reported that the U937 cell line is characterized by PI3k/Akt/mTOR hyperactivation while the OCIAML3 cell line relies mostly on the Ras/Raf/MEK/Erk pathway, we evaluated the BKM120-induced intracellular signaling modulations on this two cell lines. After 3h of BKM120 exposure, the analysis of activation status of the PI3K/Akt/mTOR pathway revealed, on the U937, the downregulation of pAkt levels at 0.5µM associated with p70 and 4EBP1 dephosphorylation at 1µM. At variance, on the OCIAML3, both effects were achieved at higher concentrations (1 and 2µM, respectively), reflecting the different sensitivity to apoptosis of this model. A limited cytotoxicity (1.2 fold increase of apoptosis) was observed on normal PBMCs isolated from healthy volunteers following BKM120 exposure. In contrast, a pro-apoptotic activity was seen at 144h on the 4 primary AML cells (5.9, 3.9, 2.2 and 2.1 fold increase of apoptosis). Moreover, a mean increase of AnnV positive cells from 13.0% ± 0.06 (vehicle) to 23.2% ± 0.15, 25.6% ± 0.15, 32.9% ± 0.1 (p=0.02) and 40.3% ± 0.13 (p=0.02) was obtained on this cells following exposure to 0.5, 1, 2 and 5μM, respectively. In conclusion, our study demonstrates, at our knowledge for the first time, that the novel pan-class I PI3K inhibitor BKM120 impairs AML cells growth and proliferation inducing a pro-apoptotic activity and inhibiting the PI3K/Akt/mTOR signaling through dephosphorylation of the key components of this pathway. Disclosures: No relevant conflicts of interest to declare.

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Pemovska, Tea, Mika Kontro, Bhagwan Yadav, Henrik Edgren, Samuli Eldfors, Agnieszka Szwajda, Henrikki Almusa et al. « Identification Of AML Subtype-Selective Drugs By Functional Ex Vivo Drug Sensitivity and Resistance Testing and Genomic Profiling ». Blood 122, n^o 21 (15 novembre 2013) : 482. http://dx.doi.org/10.1182/blood.v122.21.482.482.

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Introduction Adult acute myeloid leukemia (AML) exemplifies the challenges of modern cancer drug discovery and development in that molecularly targeted therapies are yet to be translated into clinical use. No effective second-line therapy exists once standard chemotherapy fails. While many genetic events have been linked with the onset and progression of AML, the fundamental disease mechanisms remain poorly understood. There is significant genomic and molecular heterogeneity among patients. Several targeted therapies have been investigated for improved second-line AML therapy but none has been approved for clinical use to date. It would be critically important to identify patient subgroups that would benefit from such therapies and to identify combinations of drugs that are likely to be effective. Methods To identify and optimize novel therapies for AML, we studied 28 samples from 18 AML patients with an individualized systems medicine (ISM) approach. The ISM platform includes functional profiling of AML patient cells ex vivo with drug sensitivity and resistance testing (DSRT), comprehensive molecular profiling as well as clinical background information. Data integration was done to identify disease- and patient-specific molecular vulnerabilities for translation in the clinic. The DSRT platform comprises 306 anti-cancer agents, each tested in a dose response series. We calculated differential drug sensitivity scores by comparing AML responses to those of control cells in order to distinguish cancer-specific drug effects. Next generation RNA- and exome-sequencing was used to identify fusion transcripts and mutations that link to drug sensitivities. Results Individual AML patient samples had a distinct drug sensitivity pattern, but unsupervised hierarchical clustering of the drug sensitivity profiles of the 28 AML patient samples identified 5 functional AML drug response subtypes. Each subtype was characterized by distinct combinations of sensitivities: Bcl-2 inhibitors (e.g. navitoclax; Group 1), JAK inhibitors (e.g. ruxolitinib) (Group 2) and MEK inhibitors (e.g. trametinib) (Groups 2 and 4), PI3K/mTOR inhibitors (e.g. temsirolimus; Groups 4 and 5), broad spectrum receptor tyrosine kinase inhibitors (e.g. dasatinib) (Groups 3, 4 and 5) and FLT3 inhibitors (e.g. quizartinib, sunitinib) (Group 5). Correlation of overall drug responses with genomic profiles revealed that RAS and FLT3 mutations were significantly linked with the drug response subgroups 4 and 5, respectively. Activating FLT3 mutations contributed to sensitivity to FLT3 inhibitors, as expected, but also to tyrosine kinase inhibitors not targeting FLT3, such as dasatinib. Hence, these data point to the potential synergistic combinatorial effects of FLT3 inhibitors with dasatinib for improved therapy outcome (Figure). Early clinical translational results based on compassionate use support this hypothesis. Therefore, by combinations of drugs we expect to see synergistic drug responses that can be translated into efficacious and safe therapies for relapsed AML cases in the clinic. Clinical application of DSRT results in the treatment of eight recurrent chemorefractory patients led to objective responses in three cases according to ELN criteria, whereas four of the remaining five patients had meaningful responses not meeting ELN criteria. After disease progression, AML patient cells showed ex vivo resistance to the drugs administered to the patients, as well as significant changes in clonal architecture during treatment response. Furthermore, we saw genomic alterations potentially explaining drug resistance, such as appearance of novel fusion genes. Summary The ISM approach represents an opportunity for improving therapies for cancer patients, one patient at the time. We show that the platform can be used to identify functional groups of AML linking to vulnerabilities to single targeted drugs and, importantly, unexpected drug combinations. This information can in turn be used for personalized medicine strategies and for creating hypotheses to be explored in systematic clinical trials, both for approved and investigational drugs. Disclosures: Off Label Use: Many of the compounds included in our DSRT platform are not indicated for AML therapy. Mustjoki:BMS: Honoraria, Research Funding; Novartis: Honoraria. Porkka:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Kallioniemi:Medisapiens: Membership on an entity’s Board of Directors or advisory committees; Roche: Research Funding.

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Kornblau, Steven M., Chenyu W. Hu, Suk Young Yoo, Yihua Qiu, Nianxiang Zhang, Gautam Borthakur, Naval G. Daver, Amina A. Qutub et Kevin R. Coombes. « Classification Of Acute Myelogenous Leukemia (AML) Based On Functionally Related Proteins Groups ». Blood 122, n^o 21 (15 novembre 2013) : 492. http://dx.doi.org/10.1182/blood.v122.21.492.492.

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Abstract Background In an era where the recognized heterogeneity of the pathophysiology of AML is increasing rapidly due to sequencing and other “omics” platforms, and where the number of available targeted therapeutics is also rapidly expanding, a means to individually match therapies to AML on a specific basis is needed. New targeted therapies modulate single pathways, so recognizing when a particular pathway is active is crucial, but mutations are rare within most of these pathways in AML. Furthermore pathway activation can arise by various means. Finally the interaction of multiple different activated pathways on the overall phenotype of a leukemic blast adds complexity. Methods To define the role of the pathway activation in AML we generated a custom made reverse phase protein array (RPPA) onto which were printed leukemia enriched (ficolled, CD3/CD19 depleted) cells from 511 newly diagnosed AML and 21 APL patients, including 49 with paired diagnosis and relapse samples. Both bone marrow (n=387) and peripheral blood (n=283) samples were used, with 140 cases having both. The RPPA was probed with 231 strictly validated antibodies (174 antibodies vs. total expression, 49 vs. phosphoproteins, 5 vs. cleaved forms, 3 vs. methylation sites). These proteins were divided on the basis of function into 21 Protein function groups (ProFnG) including: Apoptosis, Autophagy, Cell cycle, Creb, Cytoskeletal, Differentiation, Fli1, Hippo, Histone modifying, Hypoxia, Integrin & adhesion, MEK, P53, PI3K-AKT, PKC, SMAD, STAT, Transcription Ubiquitin and Wnt. Results Each ProFnGrp was analyzed to determine the optimal number of principal components (PrCp) and to identify noncontributory members, which were then discarded. Each PrCp (79 total) was then considered a variable and Hierarchical clustering was performed on continuous and binary signals (Sokal-Michener metric) (Figure 1). This defined 8 PrCp clusters and 8 patient groups(PatGp). Several categorical clinical features were unevenly associated with the PatGp including FAB (p=1.5e-12), WHO class (p=0.01), gender (p=0.03), Zubrod PS (p=0.005), antecedent hematological disorder (p=0.007), Cytogenetics (0.01), FLT3-ITD (p=0.003), Ras mutation (p=0.003). Likewise many continuous variables also correlated with PatGp: WBC (p=7e-14), %BM blast (p=2x10-16), % PB blast (p=2x10-16), Platelets (p=0.004), LDH (p=0.009), Albumin (p= 0.00001), Creatinine (p=0.007), CD13 (p=0.0002), CD33 (4.5xe-8), CD33 (1.1e-8). For all patients PatGp did not predict remission attainment. There was significant splay in overall survival and event free survival with median EFS durations ranging 52 , 100, 130 and 170 weeks ( p= 0.05) and in remission duration ranging from medians of 20- to 110 weeks. For intermediate cytogenetics Pat-Gps split into 4 with better outcomes (median OS 70-110 week, median RemDur 100-120 weeks) and 4 with worse outcomes (median OS 40-50 weeks, median RemDur 30-40 weeks). For unfavorable cytogenetics Pat-Gps also split into 4 with better outcomes (median OS 35-40 weeks, median RemDur 48-75 weeks) and 4 with worse outcomes (median OS 16-18 weeks, median RemDur 10-26 weeks). In a companion abstract we show the interaction between different protein functional groups. Conclusions AML could be classified based on protein functional groups. Although the classes were associated with cytogenetics the protein classifications gave prognostic information independent of cytogenetics and other traditional prognostic factors. Since this classification scheme is dependent on protein expression and functional activation states it may identify when particular pathways are being utilized and therefore be of use in triaging patients to targeted therapies. Disclosures: No relevant conflicts of interest to declare.

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Liu, Dazhi, Yonina R. Murciano-Goroff, Justin Jee, Maria E. Arcila, Darren J. Buonocore, JianJiong Gao, Debyani Chakravarty et al. « Clinicopathologic characterization of ERK2 E322K mutation in solid tumors : Implications for treatment and drug development. » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : 3135. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3135.

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3135 Background: MAPK1 encodes ERK2, a kinase component of the mitogen activated signaling (MAPK) pathway. ERK2 E322K is a known activating mutation that leads to increased phosphorylation and ERK signaling. In vitro studies found this mutation to be associated with resistance to dabrafenib, trametinib, but potential sensitivity to ERK inhibitors. Despite its potential as a drug target, little is known about the clinicopathologic characteristics of this hotspot mutation across solid tumors. Methods: Patients with solid tumors underwent tumor next-generation sequencing at Memorial Sloan Kettering Cancer Center between Jan 2015 and Sep 2020 using the MSK-IMPACT assay. Using the cBioPortal database and clinical charts, we analyzed tumors harboring MAPK1/ERK2 E322K mutations, assessed their clinicopathologic characteristics, co-mutational status and overall survival (OS). OS was measured from time of tumor sequencing to date of death or last follow-up. Results: A total of 37 tumor samples from 35 patients were identified in 59,822 tumors sequenced (0.06%) to harbor an ERK2 E322K mutation. The distribution across tumor types was as follows: head and neck squamous cell carcinoma (29%), bladder cancer (20%), lymphomas (9%), colorectal cancers (9%), gastric cancers (9%), cholangiocarcinoma (6%), cervical cancers (6%), lung cancers (6%), germ cell tumor (3%), Merkel cell carcinoma (3%), and breast cancers (3%). The OS in patients with metastatic disease and ERK2 E322K was 22.29 months (95%CI: 7.56-NA) months. Other mutations in RAS pathway frequently co-occurred with ERK2 E322K mutation (17/37, 46%). Concurrent mutations are also involved in pathways of cell cycle (71%), PI3K (71%), TP53 (66%), NOTCH (57%), RTK (51%), HIPPO (29%), TGF-beta (29%), WNT (26%), NRF2 (20%), MYC (14%). The median TMB score of samples from solid malignancies was 12.3 (range:0-101, quartiles: 6.9-33.0) mutation/Mb. Two patients (2/35, 6%) had microsatellite-instability high (MSI-H) tumors. The most frequent concurrent activating mutations include ARID1A (29%), FBXW7 (26%), PI3KCA (22%), PI3KR1/2/3 (20%), CDKN2A (11%), PTEN (8%), BRCA1/2(8%), FGFR3 (8%), BRAF (6%), Only one of these 35 patients received treatment targeting BRAF/MEK/ERK pathway and achieved partial response. One patient with NSCLC harboring a concurrent EGFR L858R mutation did not respond to erlotinib. One patient with PI3KCA mutated head and neck cancer did not respond to PI3K inhibitor. Two patients had TMB score of 100.9 and 12.9 mutation/Mb had partial response to pembrolizumab. Conclusions: ERK2 E322K mutation is a rare oncogenic mutation across diverse solid tumor types, associated with a high co-occurrence of other activating mutations and a high TMB. The lack of response to other targeted therapies suggests ERK2 E322K is a potential driver mutation. These findings may inform treatment and further development of ERK inhibitors.

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Cho, William C., Ka-Po Tse, Kien-Thiam Tan, Wah Cheuk, James C. Chow, Ka M. Cheung et Shu-Jen Chen. « Abstract 5787 : Identification of genomic alterations in lymphoepithelioma-like carcinoma by next-generation sequencing ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 5787. http://dx.doi.org/10.1158/1538-7445.am2022-5787.

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Abstract Introduction: Lymphoepithelioma-like carcinoma (LELC) is a special pathological tumor exclusive to Asians and EBV infection. As LELC is rare, the genetic picture is not very clear. Our study aims to identify the genomic alterations (GAs) and novel potential predictive biomarkers for LELC by next-generation sequencing (NGS). Materials and Methods: A retrospective search was performed to retrieve the LELC samples from Queen Elizabeth Hospital (Hong Kong SAR, China). We identified 38 pathologically confirmed LELC patients with archived surgically resected samples. Of these, 22 tissue specimens had median or heavy deamination and thus did not meet the strict sequencing quality control criteria. Deep targeted sequencing was performed in 16 LELC tissues (12 stage I, 1 stage II, 2 stage III, and 1 stage IV), using a panel of 440 cancer-related genes. Results: We identified 52 mutations, including 45 missenses, 3 splice-sites, and 4 frameshifts. The 9 most frequently mutated genes were MUC6 (43.75%), MUC16 (18.75%), LRP1B (12.5%), FRG1 (12.5%), NSD1 (12.5%), KMT2C (12.5%), ATM (12.5%), KMT2D (12.5%), and MED12 (12.5%). Copy number variant (CNV) analysis identified 172 CNVs, including 163 gains, 5 amplifications, and 4 heterozygous deletions. Gene copy number gain was common (12.5%-18.75%) in chromosome 5p (FGF10, RICTOR, IL7R, ADAMTS16, SDHA, TERT), 6p (TNF, HIST1H1C, HIST1H1E), and 12p (KRAS, SLCO1B3, SLCO1B3, CCND2, FGF23, FGF6, KDM5A, RAD52, IKZF1). These GAs were associated with 8 pathways, including the cell cycle, TP53, NOTCH, PI3K/AKT/mTOR, RTK/RAS/RAF/MEK, TGF-β, β-catenin/WNT, and DNA remodeling pathways. The NGS-derived tumor mutational burden was 1.2 muts/Mb (range 0-7.1) and no tumor exhibited a microsatellite-high signature. For actionability analysis, five patients harbored deleterious or likely deleterious mutations in HRR genes (1 ARID1A, 2 ATM, 1 BRCA2, 1 RAD51C) and thus their tumors might respond to PARP inhibitors, especially two patients with biallelic loss. One patient had concomitant CDK4 and EGFR copy number gain, suggesting a necessity blockade of CDK4/6 and EGFR. Conclusion: Our data may provide insight for understanding the molecular basis underlying LELC and may help develop potential personalized targeted therapies for LELC patients. More than 31% of the LELC cases harbored at least one actionable GA, with five potential candidates for the treatment with FDA-approved drugs for other types of cancer, making the evaluation of these GAs as potential targets for LELC worth considering in future clinical trials. Given the limited treatment options in LELC patients, comprehensive genomic profiling of tumors by NGS has the potential to identify novel treatments for precision medicine in LELC management. Citation Format: William C. Cho, Ka-Po Tse, Kien-Thiam Tan, Wah Cheuk, James C. Chow, Ka M. Cheung, Shu-Jen Chen. Identification of genomic alterations in lymphoepithelioma-like carcinoma by next-generation sequencing [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 5787.

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Sorokin, Alex, Lea Bitner, Ji Wu, David Menter, Scott Kopetz et Van Karlyle Morris. « Antitumor activity of panRAF inhibition in BRAF V600E metastatic colorectal cancer. » Journal of Clinical Oncology 35, n^o 4_suppl (1 février 2017) : 616. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.616.

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616 Background: BRAF V600E mutations, present in <10% of patients with metastatic colorectal cancer (mCRC), are associated with low responses to chemotherapy and poor survival outcomes. Targeted therapies against BRAF and EGFR have shown promising clinical activity. The panRAF inhibitor (PRI) LSN3074753 inhibits dimerization of all RAF isoforms to impede downstream MEK activation, with no reflexive MAPK reactivation common with other BRAF inhibitors. Anti-tumor activity of PRI has not been compared to BRAF + EGFR inhibition in patient-derived xenograft (PDX) models of BRAF V600E mCRC. Methods: Two PDX models of BRAF V600E mCRC (B1003 and C0999) were generated. C0999 featured a concomitant KRAS G12D mutation following resistance to the BRAF V600E kinase inhibitor vemurafenib. Mice were treated daily with oral PRI or with the combination of vemurafenib + intraperitoneal cetuximab. Tumor volumes were measured twice weekly. B1003 and C0999 cell cultures were established to test the interaction between PRI and palbociclib or BYL319 (PI3K inhibitor). Results: PRI was tolerated at a dose of 60 mg/kg and demonstrated a reduced tumor volume in the B1003 model after 28 days when compared to untreated controls (P=.03). No difference in tumor volume was seen between PRI and vemurafenib + cetuximab (P=.08). Assessment of anti-tumor activity by PRI in the vemurafenib-resistant BRAF V600E/KRAS G12D C0999 model will be reported. Cell culture from both the B1003 and C0999 models demonstrated synergism for PRI with palbociclib (ED50 .41 and .62 for the 2 models, respectively) and with BYL319 (ED50 .48 and .86, respectively). Conclusions: panRAF inhibition demonstrates similar anti-tumor activity to BRAF + EGFR inhibition in PDX models of BRAF V600E and represents a promising treatment strategy for further combination studies targeting additional critical signaling pathways in mCRC.

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Kontro, Mika, Caroline Heckman, Evgeny Kulesskiy, Tea Pemovska, Maxim Bespalov, Samuli Eldfors, Elonen Erkki et al. « Development of a Cancer Pharmacopeia-Wide Ex-Vivo Drug Sensitivity and Resistance Testing (DSRT) Platform : Identification of MEK and mTOR As Patient-Specific Molecular Drivers of Adult AML and Potent Therapeutic Combinations with Dasatinib ». Blood 118, n^o 21 (18 novembre 2011) : 2487. http://dx.doi.org/10.1182/blood.v118.21.2487.2487.

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Abstract Abstract 2487 Introduction: The molecular drivers of adult AML as well as the determinants of drug response are poorly understood. While AML genomes have recently been sequenced, many cases do not harbor druggable mutations. Treatment options are particularly limited for relapsed and refractory AML. Due to the molecular heterogeneity of the disease, optimal therapy would likely consist of individualized combinations of targeted and non-targeted drugs, which poses significant challenges for the conventional paradigm of clinical drug testing. In order to better understand the molecular driver signals, identify individual variability of drug response, and to discover clinically actionable therapeutic combinations and future opportunities with emerging drugs, we established a diagnostic ex-vivo drug sensitivity and resistance testing (DSRT) platform for adult AML covering the entire cancer pharmacopeia as well as many emerging anti-cancer compounds. Methods: DSRT was implemented for primary cells from adult AML patients, focusing on relapsed and refractory cases. Fresh mononuclear cells from bone marrow aspirates (>50% blast count) were screened in a robotic high-throughput screening system using 384-well plates. The primary screening panel consisted of a comprehensive collection of FDA/EMA-approved small molecule and conventional cytotoxic drugs (n=120), as well as emerging, investigational and pre-clinical oncology compounds (currently n=90), such as major kinase (e.g. RTKs, checkpoint and mitotic kinases, Raf, MEK, JAKs, mTOR, PI3K), and non-kinase inhibitors (e.g. HSP, Bcl, activin, HDAC, PARP, Hh). The drugs are tested over a 10,000-fold concentration range resulting in a dose-response curve for each compound and with combinations of effective drugs explored in follow-up screens. The same samples also undergo deep molecular profiling including exome- and transcriptome sequencing, as well as phosphoproteomic analysis. Results: DSRT data from 11 clinical AML samples and 2 normal bone marrow controls were bioinformatically processed and resulted in several exciting observations. First, overall drug response profiles of the AML samples and the controls were distinctly different suggesting multiple leukemia-selective inhibitory effects. Second, the MEK and mTOR signaling pathways emerged as potential key molecular drivers of AML cells when analyzing targets of leukemia-specific active drugs. Third, potent new ex-vivo combinations of approved targeted drugs were uncovered, such as mTOR pathway inhibitors with dasatinib. Fourth, data from ex-vivo DSRT profiles showed excellent agreement with clinical response when serial samples were analyzed from leukemia patients developing clinical resistance to targeted agents. Summary: The rapid and comprehensive DSRT platform covering the entire cancer pharmacopeia and many emerging agents has already generated powerful insights into the molecular events underlying adult AML, with significant potential to facilitate individually optimized combinatorial therapies, particularly for recurrent leukemias. DSRT will also serve as a powerful hypothesis-generator for clinical trials, particularly for emerging drugs and drug combinations. The ability to correlate response profiles of hundreds of drugs in clinical ex vivo samples with deep molecular profiling data will yield exciting new translational and pharmacogenomic opportunities for clinical hematology. Disclosures: Mustjoki: Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Porkka:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kallioniemi:Abbot/Vysis: Patents & Royalties; Medisapiens: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer Schering Pharma: Research Funding; Roche: Research Funding.

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Ricciardi, Maria Rosaria, Valentina Salvestrini, Roberto Licchetta, Simone Mirabilii, Maria Teresa Petrucci, Lara Rossi, Matteo Allegretti et al. « Proteomic Signature of CD34+ Cells From Chronic Myeloid Leukemia Patients ». Blood 120, n^o 21 (16 novembre 2012) : 3733. http://dx.doi.org/10.1182/blood.v120.21.3733.3733.

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Abstract Abstract 3733 The tyrosine kinase inhibitors (TKIs) represent the successful molecular therapy for patients with chronic myeloid leukemia (CML), targeting the Bcr-Abl oncogenic product. However, this disease may remain not curable for the presence of residual refractory cells, persisting during the history of the disease treatment. Several mechanisms have been associated with resistance to TKIs, including the presence of rare quiescent leukemic stem cells, less susceptible to TKIs. Moreover, Bcr-Abl activates additional downstream pathways involved in the apoptotic and proliferation control of CML cells, such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5 pathways, potentially contributing to CML TKIs drug resistance. Therefore, in this study we aimed to investigate, at the protein level, proliferative and apoptotic signal transduction pathways (STP) in CML CD34+ cells, as compared to normal CD34+ cells, in order to identify additional aberrant signals, potentially therapeutic targetable. CD34+ cells were purified from peripheral blood (PB) of five newly diagnosed, chronic phase (CP) CML patients, three normal cord blood (CB) and one leukapheretic product of a normal volunteer (PBSC). The phosphorylation status of 46 proteins from various STP and the expression of 32 proteins of the apoptotic machinery were assessed by using a customized direct phase proteome profiler antibody array. The resulting dots were visualised using ECL and quantified by densitometric analysis. CML samples were collected from patient in CP, with a WBC count ranging between 41900–135400 per microliter. The Sokal risk category was low (1/5) and intermediate (4/5). The comparison between normal CD34+ cells obtained from CB and PBSC showed that the first cells were characterized by a lower expression of STAT, Tyrosine-protein kinase and MAPK protein families. The phospho-proteomic profile of CD34+ cells from CML samples showed remarkably similarity when compared to normal CB CD34+ cells, while only two proteins resulted differently expressed in CP CD34+ cell vs. PBSC: CREB-S133, involved in the pro-survival/anti-apoptotic gene control (p=0.025) and p70S6K-T389, along the PI3k/Atk pathway and involved in the cell proliferation (p=0.049). The analysis of the 32 apoptotic proteins revealed that 10 of them were statistically significant lower in CML CD34+ cells compared to PBSC. Most of them were related to the Bcl-2 family and caspase inhibitors family, such as cIAP-1 (p=0.025), cIAP-2 (p=0.0003) and livin (p=0.016). The expression of the cyclin-dependent kinase inhibitors (CKI) was found significantly lower in CML CD34+ (p=0.05 and p=0.02 for p21/CIP1 and p27/Kip1, respectively). In conclusion, we have reported in this study that proteins and/or phosphoproteins controlling apoptosis and proliferation STP, such as Bcl-2, IAP, MAPK, PI3K/Akt, STATs and CKI families, are differentially expressed in CD34+ from CML CP, compared to PBSC. The understanding of these differences in the proteomic profile may confirm that additional multiple aberrant STP are involved in the CML and therefore must be taken into account for targeted therapies, especially of resistant cases. Disclosures: Petrucci: Jansse-Cilag, Celgene: Honoraria. Castagnetti:Novartis Pharma: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Rosti:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

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Locatelli, Silvia L., Anna Guidetti, Loredana Cleris, Silvia Tartari, Alessandro M. Gianni, Andrea Anichini et Carmelo Carlo-Stella. « The histone Deacetylase Inhibitor Givinostat in Combination with Sorafenib Induces Reactive Oxygen Species (ROS) Generation and Exerts Potent Antitumor Effects in NOD/SCID Mice with Hodgkin Lymphoma Cell Line Xenografts ». Blood 120, n^o 21 (16 novembre 2012) : 3711. http://dx.doi.org/10.1182/blood.v120.21.3711.3711.

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Abstract Abstract 3711 INTRODUCTION: Patients with refractory or relapsed classical Hodgkin Lymphoma (cHL) represent an unmet medical need and would benefit from the development of new therapies. Histone deacetylases (HDACs) and the RAF/MEK/ERK pathway are aberrantly controlled in cHL and influence a broad repertoire of tumor processes, suggesting a rationale for therapeutically targeting these pathways. We targeted these pathways using the HDAC inhibitor Givinostat (Italfarmaco S.p.A., Milan, Italy), and the RAF/MEK/ERK inhibitor Sorafenib (Nexavar, Bayer, Germany, EU) in order to investigate in vitro and in vivo the activity and mechanism(s) of action of this two-drug combination. METHODS: Three cHL cell lines, including HDLM-2, L-540 and HD-MyZ, were used to investigate the effects of Givinostat and Sorafenib, used alone or in combination, by means of in vitro assays evaluating cell growth and cell survival. Additionally, live cell imaging was used to asses the production of reactive oxygen species (ROS), and Western blotting (WB) to assess modulating effects of the two-drug combination on MAPK, PI3K/AKT, HDACs as well as the apoptotic pathways. The efficacy of Givinostat/Sorafenib combination was finally confirmed in NOD/SCID mice with cHL cell line xenografts. RESULTS: While Givinostat and Sorafenib as single agents exerted a limited activity against cHL cells, the combined Givinostat/Sorafenib treatment was associated with potent dephosphorylation of MAPK and PI3K/Akt pathways and significantly increased H3 and H4 acetylation due to a nearly complete inhibition of class I and II HDACs. Furthermore, these events were associated with a time-dependent synergistic cell growth inhibition (70% to 90%) in all Givinostat/Sorafenib-treated cHL cells. Upon Givinostat/Sorafenib exposure, HDLM-2 and L-540 cell lines showed significantly (P ≤.0001) increased levels of apoptosis (90 ± 2% and 96 ± 1%, respectively) and mitochondrial dysfunction (up to 70%, P≤.0001), as compared with single agents. Apoptosis induced by Givinostat/Sorafenib combination failed to induce processing of caspase-8, −9, −3, or cleavage of PARP, and was not reversed by the pan-caspase inhibitor Z-VADfmk, suggesting the occurrence of caspase-independent apoptosis. Besides downregulating the expression of the anti-apoptotic protein Mcl-1 and ERK1/2 phosphorylation, Givinostat/Sorafenib strongly increased expression of the BH-3 only protein Bim, compared to single treatments. These findings were dependent on a potent, early and time-dependent ROS generation (up to 60%, P≤.0001) that was synergistically induced by Givinostat/Sorafenib treatment. Additionally, pretreatment of cHL cells with the ROS inhibitor YCG063 prevented the generation of ROS as well as mitochondrial membrane depolarization along with cell death induced by the two-drug combination, suggesting that ROS generation is the triggering event in Givinostat/Sorafenib induced-cell death. In vivo Givinostat/Sorafenib treatment significantly reduced the growth of L-540 and HD-MyZ nodules, resulting in an average 35% to 65% tumor growth inhibition (P ≤.0001) compared to single treatments, in the absence of any toxicity. Interestingly, as compared to controls or treatment with single agents, the combined Givinostat/Sorafenib treatment significantly increased in vivo Bim expression (7- to 21-fold increase, P ≤.0001), resulting in a marked tumor necrosis (3- to 5-fold increase, P ≤.0001). CONCLUSIONS: The combined Givinostat/Sorafenib treatment demonstrates a potent preclinical in vitro and in vivo activity against cHL cell lines by targeting aberrant expression of HDACs and MAPK. Antitumor activity of this combination involves ROS generation and Bim upregulation and provides a rationale for clinical studies using this combination in refractory/relapsed cHL patients. Disclosures: No relevant conflicts of interest to declare.

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Talloa, Dario, Silvia Triarico, Pierpaolo Agresti, Stefano Mastrangelo, Giorgio Attinà, Alberto Romano, Palma Maurizi et Antonio Ruggiero. « BRAF and MEK Targeted Therapies in Pediatric Central Nervous System Tumors ». Cancers 14, n^o 17 (31 août 2022) : 4264. http://dx.doi.org/10.3390/cancers14174264.

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BRAF is a component of the MAPK and PI3K/AKT/mTOR pathways that play a crucial role in cellular proliferation, differentiation, migration, and angiogenesis. Pediatric central nervous system tumors very often show mutations of the MAPK pathway, as demonstrated by next-generation sequencing (NGS), which now has an increasing role in cancer diagnostics. The MAPK mutated pathway in pediatric CNS tumors is the target of numerous drugs, approved or under investigation in ongoing clinical trials. In this review, we describe the main aspects of MAPK and PI3K/AKT/mTOR signaling pathways, with a focus on the alterations commonly involved in tumorigenesis. Furthermore, we reported the main available data about current BRAF and MEK targeted therapies used in pediatric low-grade gliomas (pLLGs), pediatric high-grade gliomas (pHGGs), and other CNS tumors that often present BRAF or MEK mutations. Further molecular stratification and clinical trial design are required for the treatment of pediatric CNS tumors with BRAF and MEK inhibitors.

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Burmi, Rajpal S., Euan A. Stronach, Hani Gabra, Elaina N. Maginn et Harpreet S. Wasan. « PI3K/mTOR/MEK-targeted therapies in pancreatic and ovarian cancers ». Pancreatology 16, n^o 3 (juin 2016) : S7. http://dx.doi.org/10.1016/j.pan.2016.04.026.

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Gray, Mike J., Gloria Wangrong YangKolodji et Debu Tripathy. « Co-targeting PI3K and ras pathways in trastuzumab resistance. » Journal of Clinical Oncology 31, n^o 15_suppl (20 mai 2013) : e13515-e13515. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13515.

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e13515 Background: HER2+ breast cancers (BC) account for 20–25% of invasive BC and are associated with an aggressive phenotype and poor patient outcome. The development of trastuzumab and other HER2-targeted therapy dramatically improved outcomes for HER2-positive BC, but most patients with advanced HER2+ BC will eventually become resistant to treatment, underlying the importance of developing alternative or combination treatments. Alterations in the PI3K/mTOR/Akt pathways are cited as contributors to the development of trastuzumab resistance, however targeting these kinases as single agents has yielded less than expected clinical results. This suggests that combinational treatment with other kinase pathway inhibitors may be required, including those targeting the Ras/MAPK pathway, which is typically not mutationally activated in breast cancer. Methods: Trastuzumab resistant HER2+ BC cell lines were subjected to dose responses with the mTOR inhibitor everolimus or the AKT inhibitor MK-2206 alone or in combination with the MEK 1/2 inhibitor GSK212 and changes in EC50s determined by MTT assay. Western blot analysis was performed to assess changes in the mTOR/AKT/ MAPK pathways or apoptotic regulators accompanying single or combination treatments. Results: In 4 of 5 trastuzumab-resistant HER2+ BC cell lines, each lacking activating mutations in the Ras/Raf pathway, combination treatment with everolimus or MK-2206 with GSK212 had significantly greater efficacy than by either inhibitor alone. Furthermore, combinational treatment targeting the mTOR and AKT pathways showed only an additive effect, and was much less effective than targeting both the MEK and PI3K pathways. Western analysis showed that AKT and mTOR inhibition caused a transient increase in ERK 1/2 activity in sensitive cell lines, suggesting that treatment by mTOR or AKT inhibitors activated critical survival pathways in the MAPK signaling that were blocked by GSK212. Conclusions: Treatment with mTOR or AKT inhibitors in combination with MEK inhibitors can act in a synergistic manner with greater efficacy than each inhibitor alone. Moreover, ERK 1/2 activity may serve as a predictive biomarker in trastuzumab-refractory patients treated with mTOR/MEK or AKT/MEK doublet therapy.

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Canté-Barrett, Kirsten, Jill AP Spijkers-Hagelstein, Jessica GCAM Buijs-Gladdines, Wilco K. Smits, Rogier C. Buijsman, Guido JR Zaman, Rob Pieters et Jules PP Meijerink. « T-Cell Acute Lymphoblastic Leukemia Patients with Mutations in IL7Ra or Downstream RAS-MEK or PI3K-AKT Can be Collectively Targeted By Combination of RAS and AKT Inhibitors ». Blood 126, n^o 23 (3 décembre 2015) : 445. http://dx.doi.org/10.1182/blood.v126.23.445.445.

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Abstract Background: Pediatric T-cell acute lymphoblastic leukemia patients frequently harbor mutations in IL7Ra or downstream molecules encoded by JAK1, JAK3, N-RAS, K-RAS, NF1, AKT, and PTEN. These mutated signaling molecules can contribute to leukemia by disturbing a multitude of cellular processes such as the cell cycle, epigenetics, apoptosis, or affecting other important signal transduction pathways. Aims: We aimed to determine the overall incidence of mutations in IL7Ra and downstream signaling components in a large cohort of pediatric T-ALL patients. In order to find better treatment options for patients with these mutations, we analyzed the effect of selected IL7Ra-pathway inhibitors-individually and in combinations-on downstream signaling and cytotoxicity in Ba/F3 cells expressing each of the mutations. Methods: We sequenced 146 pediatric T-ALL patient samples for mutations in the FERM, pseudokinase and kinase domains of the Janus kinase gene family (JAK1, JAK2, JAK3, TYK2) and hotspot regions of N-RAS and K-RAS. We adapted the IL3-dependent Ba/F3 cell line to express mutant or wild type genes upon induction by doxycycline and assessed cell viability and signaling in the absence of IL3. Various IL7Ra-pathway inhibitors were tested using this system, and the synergy of combined inhibitors was determined by comparing the dose-response curve of different ratios of IC50-based inhibitor concentrations to the curves for each of the single inhibitors. The Combination Index was calculated using Calcusyn™ software. Results: IL7Ra, JAK, RAS, AKT and PTEN mutations are present in approximately 45% of patients and occur in a predominantly mutually exclusive fashion, suggesting they share aberrant activation of similar downstream targets. We found JAK1, JAK3 and RAS mutations as previously reported, but also identified new JAK1 mutations including V427M, L624YPILKV, E668Q, P815S, and T901G. A novel three-dimensional model of JAK1 reveals that mutations in JAK molecules affect important amino acids that are involved in the interaction between the pseudokinase and kinase domains, facilitating constitutive kinase activity. In our doxycycline-inducible IL3-dependent Ba/F3 system, expression of mutant genes-in contrast to the wild type genes-transforms Ba/F3 cells by supporting IL3-independent growth through activation of the RAS-MEK-ERK and PI3K-AKT pathways. We used this system to test the sensitivity to pharmacological inhibitors; IL7Ra and JAK mutant Ba/F3 cells are sensitive to JAK inhibition, so JAK inhibitors such as ruxolitinib may offer therapeutic potential for IL7Ra, JAK1 or most JAK3 mutated T-ALL patients. The RAS and AKT mutants respond to RAS-MEK and PI3K-AKT-mTOR inhibition, respectively, but are-as expected-insensitive to JAK inhibition. Remarkably, IL7Ra and JAK mutants are relatively resistant to downstream RAS-MEK-ERK or PI3K-AKT-mTOR inhibition, indicating that inhibiting just one of these downstream pathways is insufficient. We provide evidence of (cross-)activation of the alternate pathway when one of these pathways is inhibited. Combined inhibition of MEK and PI3K/AKT synergistically prevents proliferation of the IL7Ra- and JAK-mutants by efficiently blocking both downstream signaling pathways. Furthermore, this combined inhibition is cytotoxic in two out of five tested primary T-ALL specimens. Summary/Conclusion: We show that the combined inhibition of MEK and PI3K/AKT leads to strong and synergistic cytotoxic effects in the IL7Ra and JAK mutants and efficiently blocks signaling downstream of both pathways. This inhibitor combination is effective in two out of five primary T-ALL samples. Therefore, the cytotoxic effects of synergistic MEK and PI3K/AKT inhibition should be further explored as a therapeutic option for (relapsed) ALL patients. Disclosures Buijsman: Netherlands Translational Research Center B.V.: Equity Ownership, Other: founder and shareholder. Zaman:Netherlands Translational Research Center B.V.: Equity Ownership, Other: founder and shareholder.

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Niogret, Julie, Valentin Derangère, Corentin Richard, Lisa Nuttin, François Ghiringhelli, Laure Favier, Leila Bengrine Lefevre, Anthony Bergeron, Laurent Arnould et Romain Boidot. « Association of Anti-EGFR Antibody and MEK Inhibitor in Gynecological Cancer Harboring RAS Mutation : A Case Series ». International Journal of Molecular Sciences 23, n^o 6 (19 mars 2022) : 3343. http://dx.doi.org/10.3390/ijms23063343.

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Low-grade serous carcinoma represents a minority of serous carcinoma. Although they have better prognosis than high-grade serous carcinoma, they respond poorly to chemotherapy. Thus, it appears necessary to find other treatments such as targeted therapies. Since RAS or RAF mutations occur frequently in low-grade serous carcinoma and lead to constitutively activated MAPK cascade, MEK inhibition should be effective in the treatment of low-grade serous carcinoma. So, we wanted to evaluate the clinical benefit of MEK inhibitors in the management of advanced-stage low-grade serous carcinoma harboring KRAS or NRAS mutation. We report a case series of three women with advanced-stage low-grade serous carcinoma harboring RAS mutation who had stabilization of their disease during several months under targeted therapy combining anti-EGFR antibody and MEK inhibitor. We performed in vitro experiments, confirming the effectiveness of MEK inhibitor on the KRAS-mutated OVCAR-5 cell line, and the constitutively activation of MAPK cascade in RAS-mutated carcinoma. However, it seems that the anti-EGFR antibody does not provide any additional benefit. After whole exome analysis is carried out on the patient with the shortest response, we observed the appearance of RB1 loss-of-function mutation that could be a mechanism of resistance to MEK inhibitors in RAS- of RAF-mutated cancers. The MEK inhibitor is effective in the advanced stages of low-grade serous carcinoma harboring RAS mutation with acceptable tolerance. RB1 loss could be a mechanism of resistance to MEK inhibitors in RAS-mutated low-grade serous carcinoma.

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Akutagawa, Jon, Monique Dail, Lori S. Friedman, Kevin M. Shannon, Deepak Sampath et Benjamin S. Braun. « The PI3K Inhibitor GDC-0941 Attenuates Disease in a KrasG12D Mouse Model of CMML and JMML. » Blood 120, n^o 21 (16 novembre 2012) : 2862. http://dx.doi.org/10.1182/blood.v120.21.2862.2862.

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Abstract Abstract 2862 Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are overlap myelodysplastic/myeloproliferative neoplasia (MDS/MPN) syndromes that respond poorly to conventional treatment regimens. Both diseases are characterized by aberrant N-Ras, K-Ras, Cbl, and SHP-2 proteins, which are not attractive drug target candidates. Focus has shifted to downstream effector pathways, which include Raf/MEK/ERK, phosphoinositide-3-OH kinase (PI3K)/Akt, and Ral-GDS/Ral-A cascades. However, it is unclear which pathways, if any, should be targeted. In part to address this question, we previously developed a mouse model of CMML and JMML by expressing a conditional “knock-in” KrasG12D oncogene in bone marrow. Our earlier studies showed that inhibition of MEK yields a significant reduction in disease burden in this model, including reduced leukocytosis, improved anemia and enhanced survival. Here, we interrogate the role of the PI3K/Akt pathway in KrasG12D driven MPN and further explore which specific pathways are responsible for leukemogenesis due to hyperactive Ras. We administered GDC-0941, a selective PI3K inhibitor, to Mx1-Cre, KrasG12D mutant mice Mice with well established MPN and wild-type (WT) littermates were randomly chosen to receive daily oral administration of GDC-0941 or a control vehicle. Treated mice exhibited dramatic corrections of leukocytosis and anemia as well as decrease in splenomegaly. Flow cytometry of bone marrow and peripheral populations also imply that GDC-0941 treatment corrects the aberrant proliferation, amends differentiation of bone marrow progenitors, and revives ineffective erythropoiesis found in KrasG12D mice. Treatment also resulted in markedly improved survival of KrasG12D mice; virtually all KrasG12Dmice in the treatment arm outlived their control counterparts. Our data suggest PI3K inhibition may play a role in suppressing hematologic dysfunction in JMML and CMML patients. Potential crosstalk between PI3K and MEK signaling further suggest that combinatorial activities of PI3K and MEK inhibition should be investigated. Disclosures: Friedman: Genentech, Inc.: Employment. Sampath:Genentech, Inc.: Employment.

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Grimont, Adrien, David J. Falvo, Paul Zumbo, Grace Pan, John Nguyen, Rhonda K. Yantiss, Doron Betel, Laura Martin, Steven D. Leach et Rohit Chandwani. « Abstract B055 : Rac1 is essential for the maintenance of established KrasG12D-driven pancreatic ductal adenocarcinoma through senescence escape ». Cancer Research 82, n^o 22_Supplement (15 novembre 2022) : B055. http://dx.doi.org/10.1158/1538-7445.panca22-b055.

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Abstract The most prominent KRAS variants (G12D, G12V, G12R) that together represent around 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are so far undruggable. While the role of several Kras mediators have been characterized in the initiation of PDAC, very little is known about the hierarchy of Kras effectors in the maintenance of the tumor. In recent years, strategies targeting the effectors downstream of mutant KRAS have offered scope for combined inhibition of EGFR and CRAF or MEK/RAF. However, these studies, unfortunately, have been limited by either narrow interrogation of downstream effectors in mouse models, or by the use of two-dimensional cell culture systems that may not recapitulate dependencies of the tumor in situ, respectively. To systematically interrogate the potential molecular dependencies in pancreatic tumor maintenance across several combinations of driver mutations, we have deployed in vitro and in vivo approaches in which we have selectively targeted key mediators of known KRAS-dependent pathways. These include Craf, Braf, PI3K, RalA, RalB, and Rac1, for which we have used inducible GFP-coupled shRNAs in 3D mouse and human tumor organoids harboring KrasG12D and p53R172H mutation. Using competition, cell cycle, and volumetric assays, we have uncovered that Rac1, Kras, and Craf are essential to the growth of PDAC organoids, whereas Braf, PI3K, RalA and RalB are dispensable. Interestingly, Rac1 depletion led to the strongest phenotype among the Kras mediators with a reduction of macropinocytosis, cell migration and colony formation in vitro. In an orthotopic pancreatic injection model, we observed that Rac1 inhibition in vivo led to diminished primary tumor growth, improved survival, and a reduction of metastatic incidence and outgrowth. In parallel, we performed RNA-sequencing on Kras-, Craf-, Rac1-, RalA- and Renilla-depleted organoids and found that Rac1 depletion rewires tumor cells to acquire a more PanIN-like phenotype, highlighting the importance of these proteins for the maintenance of PDAC cells. We also identify in Rac1- depleted cells evidence of deregulation of reactive oxygen species (ROS) and induction of a senescence-associated secretory phenotype (SASP) compared to control organoids. With a cytokine and chemokine array, we confirmed the increase of SASP chemokines (Csf3, Cxcl1, Cxcl2 and Cxcl5) and also detected bona fide senescence via SA-βgal staining. Finally, using several Rac1 inhibitors, we recapitulate the importance of Rac1 in PDAC growth. These data suggest that among the pleiotropic signaling downstream of mutant Kras, Rac1 is a critical node in PDAC maintenance that promotes tumor cell proliferation and senescence escape. Our findings point towards future efforts to couple Rac1 inhibition to define therapeutic synergies with immunotherapy and/or radiation. All together, we anticipate these findings can inform the subsequent development of novel therapies to address these vulnerabilities. Citation Format: Adrien Grimont, David J. Falvo, Paul Zumbo, Grace Pan, John Nguyen, Rhonda K. Yantiss, Doron Betel, Laura Martin, Steven D. Leach, Rohit Chandwani. Rac1 is essential for the maintenance of established KrasG12D-driven pancreatic ductal adenocarcinoma through senescence escape [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B055.

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Allegrezza, Michael, Melanie Rutkowski, Tom Stephen, Nikos Svoronos, Amelia Tesone et Jose Conejo-Garcia. « Targeted molecular therapies for cancer : collateral damage ? (P2028) ». Journal of Immunology 190, n^o 1_Supplement (1 mai 2013) : 132.4. http://dx.doi.org/10.4049/jimmunol.190.supp.132.4.

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Abstract Much attention has been given to the idea of personalized cancer treatment, where the oncogenes driving tumor growth can be identified in each patient and targeted with specific molecular therapies. Many targeted inhibitors are in clinical development after showing promise in xenograft tumor models, but their impact on anti-tumor immunity remains unknown. Because immune cells use many of the same pathways frequently mutated in cancer (MAPK, PI3K, CDK), we hypothesized that molecular inhibition of these pathways would also detrimentally affect anti-tumor immunity. We tested a panel of over 40 molecular inhibitors on TCR-induced proliferation of human T cells and found that many of these inhibited proliferation at active concentrations nearly identical to those found when tested against tumor cells. Further analysis with PI3K and MEK inhibitors showed that their effect on T cell function varied depending on the stimulation strength and presence of certain cytokines. These findings indicate that many of these molecules may be immunosuppressive, and this knowledge can help guide the development of therapies that inhibit tumor cells while maintaining protective anti-tumor immunity in order to achieve maximum therapeutic effects.

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Queisser, Angela, Emmanuel Seront, Laurence M. Boon et Miikka Vikkula. « Genetic Basis and Therapies for Vascular Anomalies ». Circulation Research 129, n^o 1 (25 juin 2021) : 155–73. http://dx.doi.org/10.1161/circresaha.121.318145.

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Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met (hepatocyte growth factor receptor), and VEGF (vascular endothelial growth factor) A/VEGFR (vascular endothelial growth factor receptor) 2 cascades has led to the evaluation of tailored strategies with preexisting cancer drugs that interfere with these signaling pathways. The era of theranostics has started for the treatment of vascular anomalies. Registration: URL: https://www.clinicaltrialsregister.eu ; Unique identifier: 2015-001703-32.

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Comeaux, Evan, Wenwei Lin, Taosheng Chen, Burgess Freeman et Charles G. Mullighan. « PI3K and MEK Inhibition in Hypodiploid Acute Lymphoblastic Leukemia ». Blood 128, n^o 22 (2 décembre 2016) : 1635. http://dx.doi.org/10.1182/blood.v128.22.1635.1635.

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Abstract Introduction: Hypodiploid acute lymphoblastic leukemia (ALL) is a rare, high-risk subtype of B-ALL associated with poor outcome. Genomic analysis of over 130 Hypodiploid ALL patients defined the distinct genomic landscape of this disease, defining two principal subtypes including Ras-activating alterations and IKZF3 loss in near haploid tumors (24-31 chromosomes) and mutation of TP53 coupled with homozygous IKZF2 loss in low hypodiploid tumors (32-39 chromosomes). New therapies are needed to improve outcome of this disease, necessitating preclinical studies in hypodiploid tumors in vitro, ex vivo and in vivo. Hypothesis: The observation of frequent Ras pathway activating mutations in hypodiploid ALL tumors, as well as increased phosphorylation of downstream Ras signaling targets, suggests that these tumors may be susceptible to PI3K/MEK inhibition. Ras signaling target activation was observed in hypodiploid tumors irrespective of mutational status. Here we used cell lines and representative xenograft models to explore the therapeutic efficacy of inhibiting PI3K/MAPK signaling in hypodiploid ALL. Methods: The near haploid cell lines NALM-16 and MHH-CALL-2 and eight patient-derived xenograft (PDX) models (four near haploid and four low hypodiploid) were selected for preclinical studies. Xenografts were representative of the most common genomic lesions observed in hypodiploid ALL patients, including deletion of NF1, PAG1 and IKZF3 in near haploid and mutation of TP53 and IKZF2 deletion in low hypodiploid (Holmfeldt et al. Nat Genet 2013; Mullighan et al. Blood 2015). Next-gen sequencing of xenograft and diagnosis tumor DNA confirmed the presence of key genetic alterations in the xenografts. A lentiviral vector was used for stable expression of luciferase in xenograft tumors for in vivo disease burden monitoring. Cell lines were treated in vitro with PI3K, mTOR, MEK, CDK4/6 and BET inhibitors either as single agents, inhibitor combinations or combined with chemotherapeutic agents. Xenografts were treated ex vivo with single agents and in vivo with PI3K and MEK inhibitors with or without chemotherapy. Results: NALM-16 and MHH-CALL-2 cell lines were most sensitive to PI3K, mTOR and BET inhibitors with IC50 values in the sub-micromolar range (Fig. 1).Treatment of xenografts ex vivo showed near haploid and low hypodiploid tumors to be four-fold more sensitive to pan-PI3K inhibitors and PI3K/mTOR dual inhibitors compared to PI3K α and d isoform-specific inhibitors. Near haploid and low hypodiploid xenografts were sensitive to MEK and BET inhibition ex vivo, but MEK inhibitors showed weak activity in the near haploid cell lines. Treatment with CDK4/6 inhibitors either as single agents or in combination with MEK inhibitors revealed minimal efficacy. Changes in cell signaling upon treatment was assayed by phosphoflow (Fig. 2). Akt and Erk1/2 phosphorylation was variable between tumors, whereas 4E-BP1 and S6 phosphorylation was consistently elevated, suggesting strong signaling through mTOR pathways. Pan-PI3K and PI3K/mTOR dual inhibitors showed potent activity against hypodiploid ALL tumors in vitro and ex vivo, however PI3K inhibition alone was insufficient to eliminate tumors in vivo. Substantial weight loss in mice treated with PI3K/mTOR dual inhibitors limited prolonged study in vivo. MAPK inhibition showed activity in both near haploid and low hypodiploid tumors ex vivo and displayed a modest reduction in tumor growth as a single agent in vivo. Combining the MEK inhibitor GDC-0973 with dexamethasone treatment increased efficacy, but induced significantly more weight loss than either monotherapy. Conclusion: Treatment of hypodiploid cell lines and xenografts in vitro and ex vivo, respectively, with PI3K and MEK inhibitors showed promising results, however the anti-tumor effect in vivo appeared mostly cytostatic and inhibitors were not sufficient as single agents to kill the tumor cells. MEK inhibitors showed stronger activity than PI3K inhibitors on xenografts in vivo and ex vivo, but this was not significantly increased when combined with dexamethasone treatment. The notable resistance of hypodiploid cells to dexamethasone may underlie this limited efficacy in addition to the increase in GDC-0973 clearance observed upon combination. Our findings also highlight the need to consider the PK properties of agents in the preclinical setting, particularly in combinations. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Yajima, Ichiro, Mayuko Y. Kumasaka, Nguyen Dinh Thang, Yuji Goto, Kozue Takeda, Osamu Yamanoshita, Machiko Iida et al. « RAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy ». Dermatology Research and Practice 2012 (2012) : 1–5. http://dx.doi.org/10.1155/2012/354191.

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Cutaneous malignant melanoma is one of the most serious skin cancers and is highly invasive and markedly resistant to conventional therapy. Melanomagenesis is initially triggered by environmental agents including ultraviolet (UV), which induces genetic/epigenetic alterations in the chromosomes of melanocytes. In human melanomas, the RAS/RAF/MEK/ERK (MAPK) and the PI3K/PTEN/AKT (AKT) signaling pathways are two major signaling pathways and are constitutively activated through genetic alterations. Mutations of RAF, RAS, and PTEN contribute to antiapoptosis, abnormal proliferation, angiogenesis, and invasion for melanoma development and progression. To find better approaches to therapies for patients, understanding these MAPK and AKT signaling mechanisms of melanoma development and progression is important. Here, we review MAPK and AKT signaling networks associated with melanoma development and progression.

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Heavey, S., M. A. Davies, K. J. O'Byrne et K. Gately. « 8 PIK3CA mutations and response to PI3K and MEK targeted therapies in NSCLC ». Lung Cancer 79 (janvier 2013) : S3. http://dx.doi.org/10.1016/s0169-5002(13)70008-4.

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Corcoran, Ryan Bruce, Hiromichi Ebi, David P. Ryan, Jeffrey A. Meyerhardt et Jeffrey A. Engelman. « Relationship of incomplete inhibition of PI3K pathway signaling and efficacy of cetuximab in KRAS wild-type colorectal cancers. » Journal of Clinical Oncology 30, n^o 4_suppl (1 février 2012) : 462. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.462.

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462 Background: Therapies targeting receptor tyrosine kinases (RTKs) are typically effective only when they lead to simultaneous downregulation of PI3K-AKT and MEK-ERK signaling. Cetuximab is a monoclonal antibody directed against EGFR that has been approved for the treatment of metastatic colorectal cancer, and several studies have suggested that its benefit is restricted to patients with KRAS wildtype cancers. However, even in KRAS wildtype colorectal cancers, the response rate to single-agent cetuximab is low, and the mechanistic basis for this is not well-understood. Methods: The ability of cetuximab to downregulate PI3K-AKT and MEK-ERK signaling in a panel of KRAS wildtype colorectal cancer cell lines was assessed by immunoblotting. We preformed immunoprecipitations of the regulatory subunit of PI3K on lysates derived from cell lines and primary colorectal tumor specimens to identify the RTKs involved in PI3K activation. Cetuximab-based therapeutic combinations were evaluated in KRAS wildtype cell lines and tumor xenograft models. Results: Cetuximab led to effective inhibition of MEK-ERK signaling (>75% reduction in phospho-ERK), but led to incomplete inhibition of PI3K-AKT signaling (0-50% reduction in phospho-AKT) in all KRAS wildtype colorectal cell lines tested. PI3K regulatory subunit immunoprecipitations revealed multiple RTK inputs to PI3K in cell lines and primary tumors, most notably from IGFIR. Combined treatment with cetuximab and an IGFIR inhibitor or a PI3K inhibitor led to improved efficacy in vitro and in tumor xenograft models. Conclusions: Cetuximab fails to completely downregulate PI3K-AKT signaling in KRAS wildtype colorectal cancer cell lines. Biochemical analysis of cell lines and primary colorectal tumors reveals that additional RTKs other than EGFR play a role in PI3K activation in these cancers. Therefore, combining cetuximab with targeted therapies directed against the PI3K pathway may lead to improved efficacy in KRAS wildtype colorectal cancers.

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Lee, Jennifer J., Vaibhav Jain et Ravi K. Amaravadi. « Clinical Translation of Combined MAPK and Autophagy Inhibition in RAS Mutant Cancer ». International Journal of Molecular Sciences 22, n^o 22 (17 novembre 2021) : 12402. http://dx.doi.org/10.3390/ijms222212402.

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RAS (rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase (MAPK) pathways, including RAS, RAF, MEK, and ERK, have demonstrated activity in BRAF mutant and, in limited cases, RAS mutant cancer. RAS mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to RAS mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.

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Williams, Kyle B., et David A. Largaespada. « New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors ». Genes 11, n^o 5 (28 avril 2020) : 477. http://dx.doi.org/10.3390/genes11050477.

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Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

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Saberian, Chantal, Paul Sperduto et Michael A. Davies. « Targeted therapy strategies for melanoma brain metastasis ». Neuro-Oncology Advances 3, Supplement_5 (1 novembre 2021) : v75—v85. http://dx.doi.org/10.1093/noajnl/vdab131.

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Abstract Melanoma is the most aggressive of the common forms of skin cancer. Metastasis to the central nervous system is one of the most common and deadly complications of this disease. Historically, melanoma patients with brain metastases had a median survival of less than 6 months. However, outcomes of melanoma patients have markedly improved over the last decade due to new therapeutic approaches, including immune and targeted therapies. Targeted therapies leverage the high rate of driver mutations in this disease, which result in the activation of multiple key signaling pathways. The RAS-RAF-MEK-ERK pathway is activated in the majority of cutaneous melanomas, most commonly by point mutations in the Braf serine-threonine kinase. While most early targeted therapy studies excluded melanoma patients with brain metastases, subsequent studies have shown that BRAF inhibitors, now generally given concurrently with MEK inhibitors, achieve high rates of tumor response and disease control in Braf-mutant melanoma brain metastases (MBMs). Unfortunately, the duration of these responses is generally relatively short- and shorter than is observed in extracranial metastases. This review will summarize current data regarding the safety and efficacy of targeted therapies for MBMs and discuss rational combinatorial strategies that may improve outcomes further.

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Articles de revues sur le sujet « Targeted therapies, RAS, MEK, PI3K »

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