Статті в журналах з теми "BRAFV600E oncogene"
Щоб переглянути інші типи публікацій з цієї теми, перейдіть за посиланням: BRAFV600E oncogene.
Оформте джерело за APA, MLA, Chicago, Harvard та іншими стилями
Ознайомтеся з топ-50 статей у журналах для дослідження на тему "BRAFV600E oncogene".
Біля кожної праці в переліку літератури доступна кнопка «Додати до бібліографії». Скористайтеся нею – і ми автоматично оформимо бібліографічне посилання на обрану працю в потрібному вам стилі цитування: APA, MLA, «Гарвард», «Чикаго», «Ванкувер» тощо.
Також ви можете завантажити повний текст наукової публікації у форматі «.pdf» та прочитати онлайн анотацію до роботи, якщо відповідні параметри наявні в метаданих.
Переглядайте статті в журналах для різних дисциплін та оформлюйте правильно вашу бібліографію.
1
Algazi, Alain Patrick, Megan Othus, Benjamin Newell Voorhies, Kari Lynn Kendra, Shaker R. Dakhil, Amy K. Harker-Murray, Christopher D. Lao, et al. "Clinical outcomes in patients with BRAFV600 mutant melanoma and undetectable circulating tumor DNA treated with dabrafenib and trametinib." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 10059. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.10059.
Анотація:
10059 Background: Circulating tumor DNA (ctDNA) analysis has been promoted as a less-invasive surrogate assay for tumor-tissue based tumor oncogene analysis. Here, we associate detection of BRAF mutant ctDNA with PFS and OS in patients with tissue-confirmed BRAFV600 mutant melanoma enrolled in S1320, a randomized phase 2 clinical trial of continuous versus intermittent dosing of dabrafenib and trametinib. Methods: Patients with BRAFV600 melanoma received continuous therapy with dabrafenib and trametinib for 8 weeks after which patients were randomized 1:1 to proceed with intermittent treatment on a 3-week-off, 5-week-on schedule or to continue with continuous therapy. Pre-treatment blood samples were interrogated using the Guardant 360 ctDNA assay for all exons of 30 known oncogenes including BRAF and for all exons with known oncogenic mutations in the COSMIC database in 40 additional oncogenes. Clinical responses were assessed at 8-week intervals by RECIST v1.1 and PFS and OS estimates were compared using log-rank test in patients with detectable versus undetectable BRAFV600 mutant ctDNA,. Results: Somatic BRAFV600E or BRAFV600K ctDNA was detected in 34 of 50 patients with baseline (before lead-in cycle 1) blood samples available for analysis including 16 of 23 (70%) patients randomized to continuous dosing, 15 of 21 (71%) randomized to intermittent dosing, and 3 of 6 (50%) who were not randomized due to disease progression at 8 weeks or other factors. Four additional patients had other detectable somatic mutations but no detectable BRAFV600 ctDNA at baseline, and 12 patients had no detectable somatic ctDNA mutations at baseline. Detection of BRAFV600 ctDNA was associated with baseline disease stage (p = 0.008). There was no difference in the overall response rate based on baseline ctDNA detection. Detection of ctDNA at baseline was associated with worse PFS (median BRAFV600 ctDNA positive = 5.8; 95% CI: 4.2-9.6 months, BRAFV600 ctDNA negative = 21.4 mos; 95% CI 10.4-NA; measured from registration to lead-in cycle 1, p = 0.001) and OS (BRAFV600 ctDNA positive = 17.8 mos; 95% CI 9.76-NA, BRAFV600 ctDNA negative = not reached; 95% CI NA-NA, p = 0.0021). Conclusions: The absence of detectable BRAFV600 ctDNA at baseline is associated with improved PFS and OS in patients receiving treatment with dabrafenib and trametinib. Clinical trial information: NCT02196181.
2
Rogounovitch, Tatiana I., Svetlana V. Mankovskaya, Mikhail V. Fridman, Tatiana A. Leonova, Victor A. Kondratovitch, Natalya E. Konoplya, Shunichi Yamashita, Norisato Mitsutake, and Vladimir A. Saenko. "Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus." Cancers 13, no. 13 (July 5, 2021): 3374. http://dx.doi.org/10.3390/cancers13133374.
Анотація:
Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.
3
Perna, Daniele, Florian A. Karreth, Alistair G. Rust, Pedro A. Perez-Mancera, Mamunur Rashid, Francesco Iorio, Constantine Alifrangis, et al. "BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model." Proceedings of the National Academy of Sciences 112, no. 6 (January 26, 2015): E536—E545. http://dx.doi.org/10.1073/pnas.1418163112.
Анотація:
BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼80% of BRAFV600-mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of BrafV618E (analogous to the human BRAFV600E mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of BrafV618E transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes.
4
Kaabouch, Meryem, Hafsa Chahdi, Naima Azouzi, Mohammed Oukabli, Issam Rharrassi, Adil Boudhas, Hassan Jaddi, et al. "BRAFV600E hot spot mutation in thyroid carcinomas: first Moroccan experience from a single-institution retrospective study." African Health Sciences 20, no. 4 (December 16, 2020): 1849–56. http://dx.doi.org/10.4314/ahs.v20i4.40.
Анотація:
Background: The incidence of thyroid cancer is increasing worldwide at an alarming rate. BRAFV600E mutation is described to be associated with a worse prognostic of thyroid carcinomas, as well as extrathyroidal invasion and increased mortality.
Objective: To our knowledge, there are no reported studies neither from Morocco nor from other Maghreb countries re- garding the prevalence of BRAFV600E mutation in thyroid carcinomas. Here we aim to evaluate the frequency of BRAFV600E oncogene in Moroccan thyroid carcinomas.
Methods: In this Single-Institution retrospective study realized in the Anatomic Pathology and Histology Service in the Mil- itary Hospital of Instruction Mohammed V ‘HMIMV’ in Rabat, we report, using direct genomic sequencing, the assessment of BRAFV600E in 37 thyroid tumors.
Results: We detected BRAFV600E mutation exclusively in Papillary Thyroid Carcinomas ‘PTC’ with a prevalence of 28% (8 PTC out 29 PTC). Like international trends, Papillary Thyroid Carcinomas ’PTC’ is more frequent than Follicular Thyroid Carcinomas ‘FTC’ and Anaplastic Thyroid Carcinomas ‘ATC’ (29 PTC, 7 FTC and 1 ATC).
Conclusion: Our finding gives to the international community the first estimated incidence of this oncogene in Morocco showing that this prevalence falls within the range of international trends (30% to 90%) reported in distinct worldwide ge- ographic regions.
Keywords: Biomarker; BRAFV600E; Thyroid cancer; Morocco.
5
Wang, Liye, Qianyi Lu, Kuikui Jiang, Ruoxi Hong, Shusen Wang, and Fei Xu. "BRAF V600E Mutation in Triple-Negative Breast Cancer: A Case Report and Literature Review." Oncology Research and Treatment 45, no. 1-2 (November 24, 2021): 54–61. http://dx.doi.org/10.1159/000520453.
Анотація:
Background: The B-Raf proto-oncogene (BRAFV600E) gene mutation has been identified in a variety of malignancies, but no evidence of the efficacy of vemurafenib treatment in BRAFV600E mutant breast cancer (BC) has been reported. Case Presentation: We reported a 60-year-old woman with confirmed triple-negative BC with BRAFV600E mutation. Progression-free survival (PFS) for first-line chemotherapy was 7 months. The patient received vemurafenib and albumin-bound paclitaxel as second-line therapy, exhibiting regression of some pulmonary metastatic lesions with concomitant progression of other lesions, and achieved 4.4 months of PFS. Genetic testing of the progressed pulmonary lesion revealed the BRAFV600E mutation, and acquired new mutations and AR amplification. The patient ultimately died of multiple organ failure and achieved 12 months of overall survival. Conclusions: The BRAFV600E mutation may be a potential prognostic factor and therapeutic target for BC.
6
Zurnadzhy, Liudmyla, Tetiana Bogdanova, Tatiana I. Rogounovitch, Masahiro Ito, Mykola Tronko, Shunichi Yamashita, Norisato Mitsutake, Serhii Chernyshov, Sergii Masiuk, and Vladimir A. Saenko. "The BRAFV600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age." Cancers 13, no. 23 (November 30, 2021): 6038. http://dx.doi.org/10.3390/cancers13236038.
Анотація:
Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.
7
Hosier, Gregory W., and Matthew T. Roberts. "Initial response of renal cell carcinoma to vemurafenib in a patient treated for metastatic melanoma." Canadian Urological Association Journal 10, no. 9-10 (September 13, 2016): 306. http://dx.doi.org/10.5489/cuaj.3652.
Анотація:
Vemurafenib is a selective inhibitor of overactive BRAF oncogene with a substitution of lysine for glutamic acid at residue 600 (BRAFV600E), a mutation expressed in approximately 50% of all melanomas. We report a case of a patient with metastatic melanoma treated with vemurafenib, who subsequently presented with a biopsy-proven conventional renal cell carcinoma (RCC). We observed an initial complete regression of the mass while on vemurafenib. This was unexpected, given that vemurafenib is a specific inhibitor of BRAFV600E and most RCCs do not harbour this mutation.
8
Chabanet, Tamer Basel, Shannon Steinberg, Peisheng Zhang, and Mary Jo Turk. "Elucidating the oncogene-driven regulatory T cell responses during melanoma tumorigenesis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 74.1. http://dx.doi.org/10.4049/jimmunol.196.supp.74.1.
Анотація:
Abstract Regulatory T cells (Tregs) are critical mediators of tumor immune suppression. While Tregs are found in established tumors, little is known about the kinetics and dynamics of Treg accumulation and the factors promoting it during oncogene-driven tumorigenesis. The present studies characterize Treg response kinetics and conversion dynamics during early tumor development in a model of autochthonous, tamoxifen-inducible BrafV600E Pten−/− melanoma. While microscopic skin dysplasia appeared 16 days following tumor induction, FoxP3+ Treg frequency and absolute numbers accumulated by day 26, coinciding with locally-invasive neoplasm development. BrafV600E inhibition with PLX4720 prevented Treg accumulation, suggesting that oncogenic Braf controls this process. Following adoptive transfer of CD4+ T cells specific to TRP-1, antigen-specific FoxP3+ Tregs preferentially accumulated in tumor-induced skin and draining lymph nodes (dLNs), as compared to tumor-free counterparts. In contrast, depleting Tregs prior to transfer abrogated the TRP-1-specific Treg response, suggesting a predominant role for natural Tregs. Furthermore, we observed an increase in chemokine (C-C motif) ligand 17 (Ccl17) and Ccl2 prior to Treg influx to tumor-induced skin. Oncogenic Braf regulated expression of Ccl17 and Ccl2, both of which mediated Treg migration in vitro. We are currently investigating the putative role of Ccl17/2-Ccr4 chemotactic axis in Treg recruitment to sites of Braf-driven tumorigenesis in vivo.
9
Kidger, Andrew M., Linda K. Rushworth, Julia Stellzig, Jane Davidson, Christopher J. Bryant, Cassidy Bayley, Edward Caddye, Tim Rogers, Stephen M. Keyse, and Christopher J. Caunt. "Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling." Proceedings of the National Academy of Sciences 114, no. 3 (January 4, 2017): E317—E326. http://dx.doi.org/10.1073/pnas.1614684114.
Анотація:
Deregulated extracellular signal-regulated kinase (ERK) signaling drives cancer growth. Normally, ERK activity is self-limiting by the rapid inactivation of upstream kinases and delayed induction of dual-specificity MAP kinase phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that, although the MKP DUSP5 both inactivates and anchors ERK in the nucleus, it paradoxically increases and prolongs cytoplasmic ERK activity. The latter effect is caused, at least in part, by the relief of ERK-mediated RAF inhibition. The importance of this spatiotemporal interaction between these distinct feedback mechanisms is illustrated by the fact that expression of oncogenic BRAFV600E, a feedback-insensitive mutant RAF kinase, reprograms DUSP5 into a cell-wide ERK inhibitor that facilitates cell proliferation and transformation. In contrast, DUSP5 deletion causes BRAFV600E-induced ERK hyperactivation and cellular senescence. Thus, feedback interactions within the ERK pathway can regulate cell proliferation and transformation, and suggest oncogene-specific roles for DUSP5 in controlling ERK signaling and cell fate.
10
Spourquet, Catherine, Ophélie Delcorte, Pascale Lemoine, Nicolas Dauguet, Axelle Loriot, Younes Achouri, Maija Hollmén, et al. "BRAFV600E Expression in Thyrocytes Causes Recruitment of Immunosuppressive STABILIN-1 Macrophages." Cancers 14, no. 19 (September 26, 2022): 4687. http://dx.doi.org/10.3390/cancers14194687.
Анотація:
Papillary thyroid carcinoma (PTC) is the most frequent histological subtype of thyroid cancers (TC), and BRAFV600E genetic alteration is found in 60% of this endocrine cancer. This oncogene is associated with poor prognosis, resistance to radioiodine therapy, and tumor progression. Histological follow-up by anatomo-pathologists revealed that two-thirds of surgically-removed thyroids do not present malignant lesions. Thus, continued fundamental research into the molecular mechanisms of TC downstream of BRAFV600E remains central to better understanding the clinical behavior of these tumors. To study PTC, we used a mouse model in which expression of BRAFV600E was specifically switched on in thyrocytes by doxycycline administration. Upon daily intraperitoneal doxycycline injection, thyroid tissue rapidly acquired histological features mimicking human PTC. Transcriptomic analysis revealed major changes in immune signaling pathways upon BRAFV600E induction. Multiplex immunofluorescence confirmed the abundant recruitment of macrophages, among which a population of LYVE-1+/CD206+/STABILIN-1+ was dramatically increased. By genetically inactivating the gene coding for the scavenger receptor STABILIN-1, we showed an increase of CD8+ T cells in this in situ BRAFV600E-dependent TC. Lastly, we demonstrated the presence of CD206+/STABILIN-1+ macrophages in human thyroid pathologies. Altogether, we revealed the recruitment of immunosuppressive STABILIN-1 macrophages in a PTC mouse model and the interest to further study this macrophage subpopulation in human thyroid tissues.
11
Lee, Min Hee, Seong Eun Lee, Dong Wook Kim, Min Jeong Ryu, Sung Jin Kim, Sung Joong Kim, Yong Kyoung Kim, et al. "Mitochondrial Localization and Regulation of BRAFV600E in Thyroid Cancer: A Clinically Used RAF Inhibitor Is Unable to Block the Mitochondrial Activities of BRAFV600E." Journal of Clinical Endocrinology & Metabolism 96, no. 1 (January 1, 2011): E19—E30. http://dx.doi.org/10.1210/jc.2010-1071.
Анотація:
Context: The oncogenic BRAFV600E mutation results in an active structural conformation characterized by greatly elevated ERK activity. However, additional cellular effects caused by subcellular action of BRAFV600E remain to be identified. Objective: To explore these effects, differences in the subcellular localization of wild-type and mutant BRAF in thyroid cancer were investigated. Results: A significant proportion of endogenous and exogenous BRAFV600E, but not wild-type BRAF, was detected in the mitochondrial fraction, similar to other BRAF mutants including BRAFV600D, BRAFV600K, BRAFV600R, and BRAFG469A, which showed elevated kinase activity and mitochondrial localization. Induced expression of BRAFV600E suppressed the apoptotic responses against staurosporine and TNFα/cycloheximide. Interestingly, the mitochondrial localization and antiapoptotic activities of BRAFV600E were unaffected by sorafenib and U0126 suppression of MAPK kinase (MEK) and ERK activities. Similarly, although the RAF inhibitor sorafenib effectively inhibited MEK/ERK activation, it did not block the mitochondrial localization of BRAFV600E. In addition, inducible expression of BRAFV600E increased the glucose uptake rate and decreased O2 consumption, suggesting that BRAFV600E reduces mitochondrial oxidative phosphorylation, a signature feature of cancer cells. Again, these metabolic alterations resulted by BRAFV600E expression were not affected by the treatment of thyroid cells by sorafenib. Therefore, RAF and MEK inhibitors are unable to block the antiapoptotic activity of BRAFV600E or correct the high glucose uptake rate and glycolytic activity and suppressed mitochondrial oxidative phosphorylation induced by BRAFV600E. Conclusions: The mitochondrial localization observed in oncogenic BRAF mutants might be related to their altered responses to apoptotic stimuli and characteristic metabolic phenotypes found in thyroid cancer. The inability of MEK and RAF inhibitors, U0126 and sorafenib, respectively, to block the mitochondrial localization of BRAFV600E has additional therapeutic implications for BRAFV600E-positive thyroid cancers.
12
von Soosten, Laura, Janina Haar, Veronika Frehtman, Stefan Holderbach, Julius Upmeier zu Belzen, Michael Jendrusch, Konstantin Okonechnikov, et al. "THER-01. Precision brain tumor therapy by AAV-mediated oncogene editing." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i185—i186. http://dx.doi.org/10.1093/neuonc/noac079.695.
Анотація:
Abstract Pediatric high-grade glioma is a heterogeneous group of highly malignant tumors of the central nervous system, with a median overall survival of less than two years after diagnosis, demanding novel treatment options. One innovative approach is gene therapy, which has so far been hampered for cancer treatment owing to the lack of a system targeting tumor cells specifically. To overcome this limitation, we established a novel strategy for gene therapy, combining tumor cell-specific adeno-associated virus (AAV) variants with oncogene-specific CRISPR-Cas nucleases. We screened 177 different Cas9/gRNA combinations targeting the genes encoding H3K27M or BRAFV600E, and identified highly specific nucleases that edited the oncogenic allele but left the respective WT loci intact, which we validated by PCR amplicon sequencing. Next, we intravenously injected an AAV library engineered to encode its own capsid DNA into mice harboring patient-derived xenograft tumors driven by H3K27M or BRAFV600E. After 21 days, we resected neoplasms and separated mCherry-labeled tumor cells from normal surrounding cells by fluorescence-activated cell sorting. Using the DNA from tumor cells as template, we generated a second AAV library, which was utilized in another round of in vivo selection. At the end of each screen, DNA from tumor cells, surrounding cells, and control tissues (liver and spleen) was analyzed by amplicon sequencing. Strikingly, we identified multiple AAV variants that were highly and recurrently enriched in the analyzed tumor tissues. We are currently validating these variants by intravenously injecting selected, GFP-encoding AAVs to tumor-bearing mice and by subsequently analyzing their distribution throughout the aforementioned tissues. We will combine oncogene-specific nucleases with these validated AAV variants and analyze their anti-tumoral efficacy in a preclinical setting. Furthermore, we plan to adapt this approach to allografted mice, evaluating its feasibility and efficacy in syngeneic models.
13
Adamopoulos, Christos, Kostas A. Papavassiliou, Poulikos I. Poulikakos, and Athanasios G. Papavassiliou. "RAF and MEK Inhibitors in Non-Small Cell Lung Cancer." International Journal of Molecular Sciences 25, no. 9 (April 24, 2024): 4633. http://dx.doi.org/10.3390/ijms25094633.
Анотація:
Lung cancer, despite recent advancements in survival rates, represents a significant global health burden. Non-small cell lung cancer (NSCLC), the most prevalent type, is driven largely by activating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) and receptor tyrosine kinases (RTKs), and less in v-RAF murine sarcoma viral oncogene homolog B (BRAF) and mitogen-activated protein-kinase kinase (MEK), all key components of the RTK-RAS-mitogen-activated protein kinase (MAPK) pathway. Learning from melanoma, the identification of BRAFV600E substitution in NSCLC provided the rationale for the investigation of RAF and MEK inhibition as a therapeutic strategy. The regulatory approval of two RAF-MEK inhibitor combinations, dabrafenib–trametinib, in 2017, and encorafenib–binimetinib, in 2023, signifies a breakthrough for the management of BRAFV600E-mutant NSCLC patients. However, the almost universal emergence of acquired resistance limits their clinical benefit. New RAF and MEK inhibitors, with distinct biochemical characteristics, are in preclinical and clinical development. In this review, we aim to provide valuable insights into the current state of RAF and MEK inhibition in the management of NSCLC, fostering a deeper understanding of the potential impact on patient outcomes.
14
Baldari, Silvia, Giuliana Di Rocco, Marie C. Heffern, Timothy A. Su, Christopher J. Chang, and Gabriele Toietta. "Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells." Cancers 11, no. 5 (May 12, 2019): 659. http://dx.doi.org/10.3390/cancers11050659.
Анотація:
High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAFV600E). Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson’s disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAFV600E mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAFV600E mutation compared to BRAFwt acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAFV600E cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAFV600E mutation.
15
Jiang, Cuiping, Lin Xie, Yiding Zhang, Masayuki Fujinaga, Wakana Mori, Yusuke Kurihara, Tomoteru Yamasaki, Feng Wang, and Ming-Rong Zhang. "Pharmacokinetic Evaluation of [11C]CEP-32496 in Nude Mice Bearing BRAFV600E Mutation-Induced Melanomas." Molecular Imaging 17 (January 1, 2018): 153601211879595. http://dx.doi.org/10.1177/1536012118795952.
Анотація:
CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600E), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([11C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [11C]CEP-32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAFV600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [11C]CEP-32496 showed high binding affinity for BRAFV600E-positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAFV600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [11C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [11C]CEP-32496 in plasma. Our results indicate that [11C]CEP-32496 has excellent specificity and affinity for the BRAFV600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further.
16
Riesco-Eizaguirre, G., P. Gutiérrez-Martínez, M. A. García-Cabezas, M. Nistal, and P. Santisteban. "The oncogene BRAFV600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I− targeting to the membrane." Endocrine-Related Cancer 13, no. 1 (March 2006): 257–69. http://dx.doi.org/10.1677/erc.1.01119.
Анотація:
The oncogene BRAFV600E is the most frequent genetic event in papillary thyroid carcinoma (PTC) but its prognostic impact still remains to be elucidated. We evaluated a representative series of 67 individuals with PTC who underwent total thyroidectomy. BRAF-positive tumours correlated with early recurrences (32% vs 7.6%; P=0.02) during a median postoperative follow-up period of 3 years. Interestingly, within the recurrences, a significant majority had negative radioiodine (131I) total body scans, predicting a poorer outcome as treatment with 131I is not effective. This last observation led us to investigate the role of BRAFV600E and the MEK-ERK pathway in thyroid dedifferentiation, particularly in Na+/I− symporter (NIS) impairment, as this thyroid-specific plasma membrane glycoprotein mediates active transport of I− into the thyroid follicular cells. A subset of 60 PTC samples was evaluated for NIS immunoreactivity and, accordingly, we confirmed a significant low NIS expression and impaired targeting to membranes in BRAF-positive samples (3.5% vs 30%; P=0.005). Furthermore, experiments with differentiated PCCl3 thyroid cells demonstrated that transient expression of BRAFV600E sharply impaired both NIS expression and targeting to membrane and, surprisingly, this impairment was not totally dependent on the MEK-ERK pathway. We have concluded that BRAFV600E is a new prognostic factor in PTC that correlates with a high risk of recurrences and less differentiated tumours due to the loss of NIS-mediated 131I uptake.
17
Recagni, Tassinari, Doria, Cimino-Reale, Zaffaroni, Freccero, Folini, and Richter. "The Oncogenic Signaling Pathways in BRAF-Mutant Melanoma Cells are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands." Cells 8, no. 10 (October 18, 2019): 1274. http://dx.doi.org/10.3390/cells8101274.
Анотація:
Melanoma is the most aggressive and deadly type of skin cancer. Despite the advent of targeted therapies directed against specific oncogene mutations, melanoma remains a tumor that is very difficult to treat, and ultimately remains incurable. In the past two decades, stabilization of the non-canonical nucleic acid G-quadruplex structures within oncogene promoters has stood out as a promising approach to interfere with oncogenic signaling pathways in cancer cells, paving the way toward the development of G-quadruplex ligands as antitumor drugs. Here, we present the synthesis and screening of a library of differently functionalized core-extended naphthalene diimides for their activity against the BRAFV600E-mutant melanoma cell line. The most promising compound was able to stabilize G-quadruplexes that formed in the promoter regions of two target genes relevant to melanoma, KIT and BCL-2. This activity led to the suppression of protein expression and thus to interference with oncogenic signaling pathways involved in BRAF-mutant melanoma cell survival, apoptosis, and resistance to drugs. This G-quadruplex ligand thus represents a suitable candidate for the development of melanoma treatment options based on a new mechanism of action and could reveal particular significance in the context of resistance to targeted therapies of BRAF-mutant melanoma cells.
18
Uribe-Alvarez, Cristina, Daniela Araiza-Olivera, Alexa Cannon, and Jonathan Chernoff. "Abstract 4747: Novel targets for BRAFV600E and BRAFV600ERAC1P29S drug resistant melanoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4747. http://dx.doi.org/10.1158/1538-7445.am2024-4747.
Анотація:
Abstract The most common mutational drivers in malignant melanoma are the oncogene BRAFV600E/K (60%), NRASQ61L/R (30%) and the RHO GTPase RAC1P29S/L (9%). BRAFV600E/K melanoma standard of care comprises the use of checkpoint inhibitors (CPIs) such as anti-PD1 or anti-CTLA-4 in combination with targeted therapies against BRAF and MEK kinases. BRAF mutant melanomas develop intrinsic, acquired, or after treatment resistance to BRAF and MEK inhibitors : around half of targeted therapy combination treatments with anti-PD1 and 70% with anti-CTLA-4 will be unsuccessful due to melanoma intrinsic resistance. Among other causes, intrinsic drug resistance can be associated with additional genome mutations, such as the activating Rac1P29S mutation present in 6% of patients with BRAF positive melanoma. A deeper understanding on the biology, progression, and tumor microenvironment of drug resistant melanomas is needed to aid in the search of novel targets and to increase the effectivity of proposed treatments. We generated 3 sets of isogenic BRAFV600E and BRAFV600E/RAC1P29S cell lines by transfecting 501mel, 451Lu and YUMM1.7 cell lines with Rac1P29S. We then exposed them for 3 months to increasing concentrations of PLX4720 to generate drug resistant cell lines (DR). Rac1 P29S -transfected and PLX4720 resistant cell lines had an increase in the Mek/Erk signaling pathway. A differential analysis using a kinome and an epigenome drug screening library in the 501mel cell lines (501mel, 501mel Rac1P29S, 501mel-DR, 501mel Rac1P29S -DR) showed that BRAFV600E/RAC1P29S and the DR melanoma cell lines growth can be inhibited with mTor, PI3K, cdk9 and BRD4 inhibitors. BRD4 is an epigenetic regulator that recruits P-TEFb to stimulate RNA polymerase II elongation. BRD4 also interacts with SMAD3 and CDK9 to regulate transcription through eIF4G increasing oncogenic c-Myc and increasing Mek/Erk signaling pathways. We tested 501mel, 451Lu and YUMM1.7 isogenic cell line series against Rapamycin to confirm mTORC1 as an effective target. Drugs that target different subunits of the eIF4F complex (CR-1-31-B, Ribavirin and Briciclib) also decrease BRAFV600E/RAC1P29S and the DR melanoma cell lines growth specifically. Furthermore, silencing of eIF4A1 and Raptor genes reduces cell growth in the BRAFV600E/RAC1P29S, and the DR cells when compared to the parental cell lines. Silencing Rictor had no effect on cell growth on any cells. When tested in a syngraft model, CR-1-31-B and rapamycin reduced tumor size when using YUMM1.7, YUMM1.7- RAC1P29S and YUMM1.7 RAC1P29S-DR cell lines. Next, we sought to investigate the effect of inhibiting mTOR and eiF4F in the PD-1/PD-L1 axis in tumor cells and tumor associated dendritic cells and macrophages, and how targeting these modifies the tumor microenvironment. Citation Format: Cristina Uribe-Alvarez, Daniela Araiza-Olivera, Alexa Cannon, Jonathan Chernoff. Novel targets for BRAFV600E and BRAFV600ERAC1P29S drug resistant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4747.
19
Wongchenko, Matthew J., Antoni Ribas, Paolo A. Ascierto, Brigitte Dréno, Anna Maria di Giacomo, Claus Garbe, Ilsung Chang, et al. "Effects of Molecular Heterogeneity on Survival of Patients With BRAFV600-Mutated Melanoma Treated With Vemurafenib With or Without Cobimetinib in the coBRIM Study." JCO Precision Oncology, no. 2 (November 2018): 1–18. http://dx.doi.org/10.1200/po.17.00242.
Анотація:
Purpose The treatment of advanced BRAFV600-mutated melanomas with BRAF inhibitors (BRAFi) has improved survival, but the efficacy of BRAFi varies among individuals and the development of acquired resistance to BRAFi through reactivation of mitogen-activated protein kinase (MAPK) signaling is common. We performed an exploratory, retrospective analysis to investigate the effects of BRAFV600 allelic balance, coexisting oncogene mutations, cell proliferation signaling levels, and loss of PTEN expression on progression-free survival (PFS) in patients in the phase III coBRIM study, which compared the combination of the MEK inhibitor cobimetinib with the BRAFi vemurafenib versus vemurafenib as monotherapy. Methods Baseline tumor samples from the intention-to-treat population were analyzed by targeted deep sequencing at a median coverage of 3,600× and by immunohistochemistry for cell proliferation markers, BRAFV600E, and PTEN. The association of these biomarkers with PFS was assessed by Cox proportional hazards modeling. Gene expression in relation to loss of PTEN was profiled by RNA sequencing in 205 patient samples and 42 BRAFV600-mutated melanoma cell lines. Results Neither BRAFV600 allelic balance nor coexisting mutations in the RAS/RAF/RTK pathway affected PFS in either treatment group. Increased baseline MAPK signaling and cell proliferation did not affect PFS in patients treated with cobimetinib combined with vemurafenib. PTEN loss was associated with reduced PFS in patients treated with vemurafenib alone but not in patients treated with cobimetinib combined with vemurafenib. Conclusion Deeper inhibition of the MAPK pathway through targeting of both MEK and BRAF may override the effects of tumor heterogeneity and improve PFS in all patients with advanced BRAFV600 melanoma.
20
Chaft, Jamie E., Scott Swanson, Jay M. Lee, Jules Lin, Hisashi Tsukada, Tianhong Li, R. Taylor Ripley, et al. "Preliminary results of the Lung Cancer Mutation Consortium LCMC4 evaluation of actionable drivers in early stage lung cancer (LEADER) screening trial." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 8068. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.8068.
Анотація:
8068 Background: Neoadjuvant chemotherapy and immunotherapy have become standard for patients with resectable non-small cell lung cancer with no targetable oncogenic driver. For patients with tumors driven by most actionable oncogenes, little benefit has been seen. The LEADER Screening Trial designed by the LCMC and supported by the Thoracic Surgical Oncology Group aims to determine the proportion of clinical Stage IA2-III lung adenocarcinomas and adenosquamous carcinomas with one of 12 actionable oncogenes, detected through tumor and blood genomics. This abstract presents data from the first 110 tumors, all tested at Foundation Medicine. Methods: This analysis includes eligible patients on the LEADER trial with recectable NSCLC (not purely squamous) tested centrally with FoundationOneCDx (F1CDx, tissue) and/or FoundationOneLiquidCDx (F1LCDx, liquid biopsy) prior to 15Dec2023. An actionable oncogene is defined as: EGFR sensitizing or exon 20; KRAS G12C; BRAFV600E; HER2 mutation or amplification, MET ex14 skipping mutation or amplification; or RET, ROS1, ALK,or NTRK1/2/3 fusion. Detectable ct DNA was defined as tumor fraction > 0. Results: Of the 110 patients, 95% (105/110) had a successful tissue and/or liquid profiling. Of samples received, 91% (64/70) yielded successful tissue profiling, and 86% (91/ 106) successful blood profiling. All unsuccessful tests were due to inadequate DNA extraction. Some ctDNA was present in 37% (34/91) of blood samples; 62% (56/91) had no detectable. We found an actionable oncogenic driver in 35% (38/110, 95% confidence interval 26-44%) of patients tested. If any ctDNA was detected in blood, there was a 100% agreement with tumor tissue whether a driver was present or absent. In blood samples without paired tumor, an actionable alteration was found in 19% of cases (8/42). Identified driver alterations included: 12 EGFR sensitizing, 12 KRAS G12C, 4 EGFRexon 20 insertions, 2 BRAFV600E, 2 RET fusions, 2 HER2 mutations, 1 ALK fusion, 1 HER2 amplification, 1 MET ex14 skipping, and 1 ROS1 fusion. Alterations detected on liquid biopsy included EGFRexon 20 insertion, EGFR sensitizing mutations, KRAS G12C, RETfusion, and HER2 mutation. Conclusions: In this national study using both tissue and blood NGS testing, actionable oncogenic drivers were found in 35% of patients with clinical stages IA2-III lung adenocarcinoma at diagnosis. Blood testing identified an actionable driver 19% of the time when tumor testing was not done. Comprehensive genomics testing on patients with early-stage lung cancer should be standard. It identifies relevant oncogenic drivers and provides important ‘negative selection’ to identify the patients appropriate for neoadjuvant chemoimmunotherapy. Accrual to the LEADER trial continues. Clinical trial information: NCT04712877 .
21
Tosios, Konstantinos I., Eleni-Marina Kalogirou, and Ioannis G. Koutlas. "Association of MDM2 Overexpression in Ameloblastomas with MDM2 Amplification and BRAFV600E Expression." International Journal of Molecular Sciences 25, no. 4 (February 13, 2024): 2238. http://dx.doi.org/10.3390/ijms25042238.
Анотація:
Ameloblastoma is a rare tumor but represents the most common odontogenic neoplasm. It is localized in the jaws and, although it is a benign, slow-growing tumor, it has an aggressive local behavior and high recurrence rate. Therefore, alternative treatment options or complementary to surgery have been evaluated, with the most promising one among them being a targeted therapy with the v-Raf murine sarcoma viral oncogene homologue B (BRAF), as in ameloblastoma the activating mutation V600E in BRAF is common. Studies in other tumors have shown that the synchronous inhibition of BRAF and human murine double minute 2 homologue (MDM2 or HDM2) protein is more effective than BRAF monotherapy, particularly in the presence of wild type p53 (WTp53). To investigate the MDM2 protein expression and gene amplification in ameloblastoma, in association with BRAFV600E and p53 expression. Forty-four cases of ameloblastoma fixed in 10% buffered formalin and embedded in paraffin were examined for MDM2 overexpression and BRAFV600E and p53 expression by immunohistochemistry, and for MDM2 ploidy with fluorescence in situ hybridization. Sixteen of forty-four (36.36%) cases of ameloblastoma showed MDM2 overexpression. Seven of sixteen MDM2-positive ameloblastomas (43.75%) were BRAFV600E positive and fifteen of sixteen MDM2-positive ameloblastomas (93.75%) were p53 negative. All MDM2 overexpressing tumors did not show copy number alterations for MDM2. Overexpression of MDM2 in ameloblastomas is not associated with MDM2 amplification, but most probably with MAPK activation and WTp53 expression. Further verification of those findings could form the basis for the use of MDM2 expression as a marker of MAPK activation in ameloblastomas and the trial of dual BRAF/MDM2 inhibition in the management of MDM2-overexpressing/BRAFV600E-positive/WTp53 ameloblastomas.
22
Stocksdale, Brian, Yaping Joyce Liao, Gwen Coffey, and Seema Nagpal. "INNV-06. SECOND GENERATION BRAF/MEK INHIBITION IN ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii117—ii118. http://dx.doi.org/10.1093/neuonc/noaa215.490.
Анотація:
Abstract BACKGROUND Up to 65% of anaplastic pleomorphic xanthoastrocytomas (A-PXA) harbor the BRAFV600E oncogene. Trials and case series have demonstrated that BRAF-mutant gliomas, including A-PXAs, can be responsive to the first generation BRAF inhibitors dabrafenib and vemurafenib, with an ORR ranging from 26–43%. The second generation BRAF/MEK inhibitor combination encorafenib/binimetinib improves systemic outcome in melanoma patients, has better tolerability, and may have better intracranial activity compared to first generation drugs. METHOD We review the three patients with BRAFV600E A-PXA treated with encorafenib/binimetinib in our practice. RESULTS Two patients were diagnosed with A-PXA in 2014 and one in 2013. The presence of BRAFV600E was confirmed by molecular testing. All patients have received prior surgery, chemotherapy, and radiation and were at a recurrence when BRAF/MEK inhibition was initiated. One patient had CR after 2 months on treatment and remains in CR at 1-year. One patient, who is also receiving bevacizumab, has a PR, with continued clinical and imaging improvement at 6 months. Our third patient had a PR at 2 months and remains on therapy, currently 3 months post-initiation. All 3 patients report improvement in symptoms. The patient who has been on treatment for 1 year experienced rapid onset bilateral multifocal sub-retinal fluid collections followed by rapid resolution, without intervention, within days of starting treatment. This patient has also had mild decrease in EF over time. We will present continued follow up. CONCLUSIONS Encorafenib/binimetinib appears feasible, with 3 of out 3 patients with BRAFV600E A-PXA demonstrating radiographic response; 2 of these patients have durable responses. We stress the importance of a clear lab, cardiac, ophthalmologic, and dermatologic monitoring regimen as side effects can be rapid and severe. Prospective studies with encorafenib/binimetinib in BRAF-mutant primary CNS tumors are underway, and we eagerly anticipate their RESULTS:
23
Dimitrion, Peter, Jugmohit Toor, James Ge, Qiyan Wang, Carl E. Allen, Li Zhou, and Qing-Sheng Mi. "HDAC3 Is Required for Pathognomonic Features of Langerhans Cell Histiocytes." Blood 142, Supplement 1 (November 28, 2023): 676. http://dx.doi.org/10.1182/blood-2023-185195.
Анотація:
Langerhans cell histiocytosis (LCH) is a pediatric inflammatory myeloid neoplasm that develops due to dysregulated myeloid cell development. BRAFV600E is the most common disease-causing mutation and constitutively activates the mitogen-activated protein kinase (MAPK) pathway in myeloid lineage precursors leading to the key pathognomonic features of LCH cells. Enhanced myelopoiesis and reduced CCR7 expression promote accumulation of LCH cells in tissues by simultaneously increasing the production of pathological DCs and preventing tissue egress. Furthermore, LCH cells acquire an oncogene induced senescence-associated secretory phenotype (SASP) that depends on mammalian target of rapamycin (mTOR), which is hallmarked by increased expression of anti-apoptotic proteins, inflammatory cytokines, and matrix metalloproteinases enhancing survival of LCH cells and promoting recruitment of inflammatory immune cells forming characteristic granulomatous lesions. These pathognomonic features result in the accumulation of LCH cells in any organ causing a wide range of clinical symptoms. Frontline therapy for LCH involves combination chemotherapy and steroidal anti-inflammatories, or MAPK inhibitors, which have significant toxicity and fail to eliminate disease causing precursors. New therapeutic approaches are urgently needed. Here, using multiple genetic mouse models, we show that normal epidermal Langerhans cells (LCs) depend on HDAC3 for their development, differentiation, and survival. Integrative RNA and chromatin-immunoprecipitation-sequencing show loss of HDAC3 abrogates the expression of master regulators of myeloid development and function including Csf1r, Spi1, Id2 and Runx3. LCH cells are also known to rely on Csf1r and Pu.1 for their development and homeostasis, thus we hypothesized that LCH cells similarly rely on HDAC3 for their development and survival. CD11c Cre LSL-BRAFV600E ( BRAFV600E CD11c) mice develop severe multifocal LCH with pronounced lesion development in their livers and lungs, hepatosplenomegaly, and a reduced lifespan due to the accumulation of pathological dendritic cells (DCs). We generated BRAFV600E CD11c HDAC3 fl/fl ( BRAFV600E HD3KO) mice, which produce pathological DCs that simultaneously express BRAFV600E and harbor a conditional deletion in the deacetylase domain of HDAC3. Compared to BRAFV600E CD11c mice, BRAFV600E HD3KO mice exhibited significantly less hepatosplenomegaly, reduced lesional burden (Panel A), attenuated disease progression, and improved survival indicating reduced LCH disease burden. Compared to BRAFV600E CD11c flow cytometry showed BRAFV600E HD3KO had reduced numbers of LCH cells in lungs and livers linking improved disease outcomes to abrogation of pathological DCs. Flow cytometric analysis of circulating myeloid cells further found reduced frequency of circulating DCs and DC progenitors, indicating that a lack of HDAC3 activity prevents the development of pathological DCs (Panel B). LCH-like cells can be generated in vitro by culturing BRAFV600E CD11c bone marrow with granulocyte-monocyte colony-stimulating factor (GM-CSF), providing a valuable drug screening tool. Treating LCH-like cells with RGFP966, an HDAC3-specific inhibitor, increased apoptosis indicated by annexin-V and DAPI staining, reduced expression of Bcl-2, increased CCR7 expression, and decreased S6 phosphorylation (an indication of decreased mTOR activity), showing that pharmacological inhibition of HDAC3 may prove therapeutically efficacious by abrogating pathognomonic features of LCH cells. Together, our findings identify HDAC3 as a critical epigenetic regulator for both healthy and pathological LCs. We further show, HDAC3 is required for multiple pathognomonic features of LCH cells and could be a promising drug target. Furthermore, if HDAC3 is required for the development of pathological DC and DC progenitors, HDAC3 blockade would address a great need in treatment of patients with LCH.
24
Cangi, Maria Giulia, Riccardo Biavasco, Giulio Cavalli, Greta Grassini, Elena Dal-Cin, Corrado Campochiaro, Barbara Guglielmi, et al. "BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease." Annals of the Rheumatic Diseases 74, no. 8 (March 26, 2014): 1596–602. http://dx.doi.org/10.1136/annrheumdis-2013-204924.
25
Hassan, Alaa A., Nasr K. Mohamed, Ashraf A. Aly, Mohamed Ramadan, Hesham A. M. Gomaa, Ahmed T. Abdel-Aziz, Bahaa G. M. Youssif, Stefan Bräse, and Olaf Fuhr. "Synthesis and Antiproliferative Potential of Thiazole and 4-Thiazolidinone Containing Motifs as Dual Inhibitors of EGFR and BRAFV600E." Molecules 28, no. 24 (December 5, 2023): 7951. http://dx.doi.org/10.3390/molecules28247951.
Анотація:
Thiazole and thiazolidinone recur in a wide range of biologically active compounds that reach different targets within the context of tumors and represent a promising starting point to access potential candidates for treating metastatic cancer. Therefore, searching for new lead compounds that show the highest anticancer potency with the fewest adverse effects is a major drug-discovery challenge. Because the thiazole ring is present in dasatinib, which is currently used in anticancer therapy, it is important to highlight the ring. In this study, cycloalkylidenehydrazinecarbothioamides (cyclopentyl, cyclohexyl, cyclooctyl, dihydronapthalenylidene, flurine-9-ylidene, and indolinonyl) reacted with 2-bromoacetophenone and diethylacetylenedicarboxylate to yield thiazole and 4-thiazolidinone derivatives. The structure of the products was confirmed by using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray analyses. The antiproliferative activity of the newly synthesized compounds was evaluated. The most effective inhibitory compounds were further tested in vitro against both epidermal growth factor receptor (EGFR) and B-Raf proto-oncogene, serine/threonine kinase (BRAFV600E) targets. Additionally, molecular docking analysis examined how these molecules bind to the active sites of EGFR and BRAFV600E.
26
Sigaud, Romain, Florian Selt, Thomas Hielscher, Nina Overbeck, Diren Usta, Marc Remke, Daniel Picard, et al. "LGG-14. MULTI-OMIC ANALYSIS OF MAPK ACTIVATION IN PEDIATRIC PILOCYTIC ASTROCYTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii368. http://dx.doi.org/10.1093/neuonc/noaa222.396.
Анотація:
Abstract Pilocytic astrocytomas (PA) are low-grade gliomas (pLGG) and are the most frequent childhood brain tumors. They are characterized by oncogene-induced senescence (OIS) initiated and sustained by senescence-associated secretory phenotype (SASP) factors. OIS and SASP in PA are thought to be driven by aberrations of the mitogen-activated protein kinase (MAPK) pathway (e.g. KIAA1549:BRAF fusion, BRAFV600E mutation, for the most common MAPK alterations occuring in PA), leading to its sustained activation. The MAPK pathway cascade is activated in a sequential manner: 1) ERK activation, which phosphorylates downstream partners in both cytoplasm and nucleus. 2) ERK-mediated induction of immediate early genes encoding transcription factors. 3) Induction of MAPK target genes expression. 4) Activation of downstream pathways. Our aim is to unravel the molecular partners involved at each level of the sustained MAPK pathway activation in pLGG with different genetic backgrounds (KIAA1549:BRAF fusion and BRAFV600E mutation), and leading to the induction of OIS and SASP factors expression. pLGG cell lines DKFZ-BT66 (KIAA1549:BRAF) and BT-40 (BRAFV600E) were treated with the MEK inhibitor trametinib at key time points, and gene expression profile analysis was performed, allowing transcriptome analysis at each step of the MAPK cascade. This will be combined with a whole proteomic and phospho-proteomic analysis. Combination of the transcriptome and proteome data layers will allow the identification of a) downstream targetable partners activated by the MAPK pathway involved in PA senescence, b) new putative targets that might bring benefit in combination with MAPK inhibitors.
27
Grob, Sydney, Lianna Nobre, Kurtis Davies, Scott Ryall, Dara Aisner, Lindsey Hoffman, Shadi Zahedi, et al. "LGG-34. CLINICAL AND MOLECULAR CHARACTERIZATION OF A MULTI-INSTITUTIONAL COHORT OF PEDIATRIC SPINAL CORD LOW-GRADE GLIOMAS." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii373. http://dx.doi.org/10.1093/neuonc/noaa222.416.
Анотація:
Abstract BACKGROUND The MAPK/ERK pathway is involved in cell growth and proliferation, and mutations in the BRAF paralog of this pathway have made it an oncogene of interest in pediatric cancer. Previous studies have identified that BRAF mutations as well as BRAF-KIAA1549 fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic aberrations in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG. METHODS We analyzed 46 spinal LGGs from children age 1–25 years from two institutions, Children’s Hospital Colorado (CHCO) and The Hospital for Sick Children (Sick Kids) for the presence of BRAF fusions or mutations. Data was correlated with clinical information. A 67 gene panel additionally screened for other possible genetic abnormalities of interest in the patient cohort from CHCO. In the Sick Kids cohort, BRAFV600E was tested for by ddPCR and IHC while BRAF fusions where detected by FISH, RT-PCR or Nanostring platform. RESULTS Of the 31 patient samples who underwent fusion analysis, 13 (42%) harbored the BRAF-KIAA1549 fusion. Overall survival (OS) for patients confirmed positive for BRAF-KIAA1549 was 100% compared to 76% for fusion negative patients. Other mutations of interest were also identified in this patient cohort including BRAFV600E, STK11, PTPN11, H3F3A, APC, TP53, PIK3CA (polymorphism), FGFR1, and CDKN2A deletion. CONCLUSION BRAF-KIAA1549 was seen in higher frequency than BRAFV600E or other genetic aberrations in pediatric spinal LGGs and trends towards longer OS although not statistically significant.
28
Sadangi, Shreyans, Katarina Milosavljevic, Edgardo Castro-Perez, Marcos Lares, Mithalesh Singh, Sarah Altameemi, David J. Beebe, Jose M. Ayuso, and Vijayasaradhi Setaluri. "Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes." Cancers 14, no. 5 (February 27, 2022): 1233. http://dx.doi.org/10.3390/cancers14051233.
Анотація:
BRAFV600E is the most common mutation driver in melanoma. This mutation is known to cause a brief burst of proliferation followed by growth arrest and senescence, which prevent an uncontrolled cell proliferation. This phenomenon is known as oncogene-induced senescence (OIS) and OIS escape is thought to lead to melanomagenesis. Much attention has been focused on the melanocyte-intrinsic mechanisms that contribute to senescence escape. Additional genetic events such as the loss of tumor suppressor PTEN and/or epigenetic changes that contribute to senescence escape have been described. However, the role of the skin microenvironment—specifically, the role of epidermal keratinocytes—on melanomagenesis is not fully understood. In this study, we employ a microfluidic platform to study the interaction between melanocytes expressing the BRAFV600E mutation as well as keratinocytes and dermal fibroblasts. We demonstrate that keratinocytes suppress senescence-related genes and promote the proliferation of transformed melanocytes. We also show that a keratinocyte-conditioned medium can alter the secretion of both pro- and anti-tumorigenic factors by transformed melanocytes. In addition, we show that melanocytes and keratinocytes from donors of white European and black African ancestry display different crosstalks; i.e., white keratinocytes appear to promote a more pro-tumorigenic phenotype compared with black keratinocytes. These data suggest that keratinocytes exert their influence on melanomagenesis both by suppressing senescence-related genes in melanocytes and by affecting the balance of the melanocyte-secreted factors that favor tumorigenesis.
29
Alaali, Lujain A., Ming Yuan, Chales Eberhart, and Eric Raabe. "Abstract 3414: The pan-RAF inhibitor tovorafenib suppresses NF1-mutant glioma through upregulation of FOXO1 and triggering of oncogene-induced senescence." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3414. http://dx.doi.org/10.1158/1538-7445.am2023-3414.
Анотація:
Abstract Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Patients with pLGG often have significant lifelong disabilities due to the location of the tumor and tumor treatments, including surgery, chemotherapy, and radiation. The most common mutations in pLGG are in the mitogen-activated protein kinase MAPK pathway, including the neurofibromin, and the BRAF oncgene. Tovorafenib (pan-RAF inhibitor) has demonstrated promising pre-clinical results in multiple cancers. Tovorafenib targets monomeric and dimeric forms of wild-type and BRAF mutants. Our objective is to investigate the effects of tovorafenib in pLGG, comparing the response of cells with BRAFV600E compared to NF1-mutant cells with wild-type RAF. JHH-NF1-PA1 is a neurofibromin (NF1) mutant line derived from a patient with germline type 1 neurofibromatosis, and JHH-PXA-1 has the BRAFV600E mutation. In addition to tovorafenib, we also tested TAK632, a tool compound that targets RAF and has a different structure . We measured readouts such as pERK and pMEK, pS6 and pAKT473 by Western blot. We treated our cells with 100 nM tovorafenib for 2 hours and 4 hours, and we found an increase of pERK (P=0.0037) and pAKT473 in JHH-NF1-PA1 but a significant decrease pERK in JHH-PXA-1 “BRAF mutant”. We also, tested TAK632 at 100 nM for 4 hrs, and found a decrease of pERK and pAKT protein level in both cell lines. Tovorafenib caused an increase of growth in JHH-NF1-PA1 cells at 100 nM and 200 nM by eighteen percent (P<0.05) and twenty-five percent (P<0.05), respectively. We detect the IC50 value at 600 nM for NF1 mutant cell line. The JHH_PXA1 cell line did not show cell growth increase in any of the lower concentrations and the IC50 was approximately 400 nM. In JHH-NF1-PA1, we observe activation in AKT and ERK in Western blot at concentrations of 500nM, 1000nM and1500nM, but downregulation at 2000nM. We further investigated the relationship between AKT and ERK phosphorylation, and the cell growth inhibition in NF1 mutant cells. FOXO1 protein induces cell cycle arrest at G1 by modulating the expression of the CDK. FOXO1 status can be regulated by AKT and ERK phosphorylation. We observed increases of total FOXO1 as well asFOXO1 phosphorylation and acetylation with increasing tovorafenib concentrations in NF1-mutant glioma. Phosphorylation and acetylation are associated with increased activity and DNA binding of FOXO1. We also detected an increase of p21CIP1 with tovorafenib treatment, suggesting the induction of senescence, which is a known effect of activated FOXO1. Additional studies investigating the induction of senescence downstream of tovorafenib are underway. We are currently planning to test tovorafenib against orthotopic xenografts of NF1 mutant glioma compared to BRAFV600E mutant glioma. Our data suggest that tovorafenib may act differently in NF1 mutant cells compared to BRAFV600E mutant cells. Citation Format: Lujain A. Alaali, Ming Yuan, Chales Eberhart, Eric Raabe. The pan-RAF inhibitor tovorafenib suppresses NF1-mutant glioma through upregulation of FOXO1 and triggering of oncogene-induced senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3414.
30
Alaali, Lujain, Eric Raabe, Micah Maxwell, Charles Eberhart, and Hui Zhang. "DDDR-18. COMPREHENSIVE PROTEOMIC PROFILING OF BRAFV600E GLIOMA CELLS SHOWS UPREGULATION OF GLYCOLYSIS AND TCA CYCLE PROTEINS AFTER COMBINED MTOR AND MAP KINASE PATHWAY BLOCKADE." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii102. http://dx.doi.org/10.1093/neuonc/noac209.383.
Анотація:
Abstract Low-grade gliomas (LGG) are slow-growing tumors that affect neurologic function by pressing on the surrounding parts of the brain. Pediatric low-grade glioma (pLGG) is the most common childhood brain tumors. Patients with pLGG often have a significant life-long disabilities. The most common mutations in pLGG are in the mitogen-activated protein kinase (MAPK) pathway including tumor suppressor neurofibromin (NF1), and the oncogene BRAF. BRAF activates MEK1/2, which activates of ERK1/2, leading to tumorigenesis. BRAFV600E mutation results in the activation segment of the kinase “monomeric form of BRAF”, leading to constitutive activation of MAP kinase and mTOR pathways Combination treatment of TAK228 (mTOR inhibitor) and trametinib (MEK1/2 inhibitor), suppressed both mTOR and MAP kinase pathways and inhibited BRAFV600E glioma tumor growth. To further investigate and understand the molecular mechanism of TAK228 and trametinib combinatorial efficacy, we performed comprehensive proteomic analysis of BRAFV600E glioma tumors treated with TAK228 and trametinib. We found increased levels of many proteins in the glycolysis and TCA cycle. Specifically we found increases at the protein level in citrate synthase, aconitase and malate dehydrogenase in the TCA cycle. In glycolysis, we observed increased glucose transporter expression (SLC2A1), increased hexokinase 2, and increased GAPDH. Upregualtion of these proteins may represent attempts to bypass the effects of mTOR and MAP kinase blockade on the activity of these pathways. We are currently performing flux metabolic profiling using uniformly labeled glucose to assess the activity of the pathways after combined mTOR and MAP kinase blockade. Our results may increase our understanding of how glioma cells use glucose and how mTOR and MAP kinase pathway inhibition affects basic metabolic pathways in glioma cells.
31
Temprine, Kelsey, Nathaniel R. Campbell, Richard Huang, Erin M. Langdon, Theresa Simon-Vermot, Krisha Mehta, Averill Clapp, Mollie Chipman та Richard M. White. "Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance". Science Signaling 13, № 629 (28 квітня 2020): eaau1453. http://dx.doi.org/10.1126/scisignal.aau1453.
Анотація:
The DNA polymerase Polκ plays a key role in translesion synthesis, an error-prone replication mechanism. Polκ is overexpressed in various tumor types. Here, we found that melanoma and lung and breast cancer cells experiencing stress from oncogene inhibition up-regulated the expression of Polκ and shifted its localization from the cytoplasm to the nucleus. This effect was phenocopied by inhibition of the kinase mTOR, by induction of ER stress, or by glucose deprivation. In unstressed cells, Polκ is continually transported out of the nucleus by exportin-1. Inhibiting exportin-1 or overexpressing Polκ increased the abundance of nuclear-localized Polκ, particularly in response to the BRAFV600E-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAFV600E melanoma cells. These observations were analogous to how Escherichia coli encountering cell stress and nutrient deprivation can up-regulate and activate DinB/pol IV, the bacterial ortholog of Polκ, to induce mutagenesis that enables stress tolerance or escape. However, we found that the increased expression of Polκ was not excessively mutagenic, indicating that noncatalytic or other functions of Polκ could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Polκ might prevent drug resistance in some cancer cells.
32
Song, Kai, Jenna K. Minami, Arthur Huang, Siavash R. Dehkordi, Shirley H. Lomeli, Jens Luebeck, Mark H. Goodman, et al. "Plasticity of Extrachromosomal and Intrachromosomal BRAF Amplifications in Overcoming Targeted Therapy Dosage Challenges." Cancer Discovery 12, no. 4 (December 20, 2021): 1046–69. http://dx.doi.org/10.1158/2159-8290.cd-20-0936.
Анотація:
Abstract Focal amplifications (FA) can mediate targeted therapy resistance in cancer. Understanding the structure and dynamics of FAs is critical for designing treatments that overcome plasticity-mediated resistance. We developed a melanoma model of dual MAPK inhibitor (MAPKi) resistance that bears BRAFV600 amplifications through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring BRAFV600E FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of preexisting subpopulations. Plasticity is not exclusive to ecDNAs, as cells harboring HSRs exhibit drug addiction–driven structural loss of BRAF amplicons upon dose reduction. FA mechanisms can couple with kinase domain duplications and alternative splicing to enhance resistance. Drug-responsive amplicon plasticity is observed in the clinic and can involve other MAPK pathway genes, such as RAF1 and NRAS. BRAF FA-mediated dual MAPKi–resistant cells are more sensitive to proferroptotic drugs, extending the spectrum of ferroptosis sensitivity in MAPKi resistance beyond cases of dedifferentiation. Significance: Understanding the structure and dynamics of oncogene amplifications is critical for overcoming tumor relapse. BRAF amplifications are highly plastic under MAPKi dosage challenges in melanoma, through involvement of de novo genomic alterations, even in the HSR mode. Moreover, BRAF FA-driven, dual MAPKi–resistant cells extend the spectrum of resistance-linked ferroptosis sensitivity. This article is highlighted in the In This Issue feature, p. 873
33
Corso, Giovanni, Valeria Pascale, Giuseppe Flauti, Daniele Marrelli, and Franco Roviello. "Oncogenic mutations in colorectal cancer, indications for anatomical sites, and targeted intervention." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22037-e22037. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22037.
Анотація:
e22037 Background: Oncogenic mutations, such as KRAS, in colorectal cancer patients are considered standard molecular biomarkers that predict the clinical benefit for the targeted intervention with EGFR inhibitors. In addition, these mutations are associated with specific anatomical area in the colon tumor development, as BRAF mutations with the microsatellite instability. Methods: In this translational study we aim to assess the mutation frequencies of the EGFR [hotspot area and polyadenine deletions (A13_del)], KRAS, BRAFV600E, and PIK3CA oncogenes in a series of 280 colorectal cancer patients. Microsatellite instability phenotype is considered in this series. All patients' clinicopathological data were considered for statistical analysis and associations. Results: In this study, we verified multiple associations between oncogenic mutations and specified clinicopathological tumor features. Respectively, we identified the following significant results: 1) EGFR A13_deletions are associated with right colon carcinoma (22.2% vs. 3.3%; p<0.005), mucinous histotype (16% vs. 7.8%; p=0.042), G3 grading (19% vs. 7.3%; p=0.024) and microsatellite instability status (p<0.005); 2) PIK3CA mutations are related mucinous histotype (12% vs. 4.4%; p=0.021) 3) KRASG12 and KRASG13mutations are correlated respectively with the left (91.4% vs. 59.3%) and right (40.7% vs. 8.6%) colon cancer development (p<0.005), and finally 4) microsatellite instability is associated with right colon tumors (28.4% vs. 5.5%; p<0.005). Conclusions: Mostly, we verified a high frequency rate of the KRASG13 and EGFR A13_del oncogene mutations in right colon cancer; whereas KRASG12 codon mutation occurs more frequently in left colon cancers. In particular, we assessed that right colon cancer is associated with specific molecular characteristics, in comparison to left colon tumors. These evidences, in association with specific clinicopathological data, can delineate novel approaches for the colorectal cancer classification and targeted intervention.
34
Ngiow, Shin Foong, Katrina M. Meeth, Kimberley Stannard, Deborah S. Barkauskas, Gideon Bollag, Marcus Bosenberg, and Mark J. Smyth. "Co-inhibition of colony stimulating factor-1 receptor and BRAF oncogene in mouse models of BRAFV600E melanoma." OncoImmunology 5, no. 3 (December 10, 2015): e1089381. http://dx.doi.org/10.1080/2162402x.2015.1089381.
35
Luciano, Angelo, Luigi Liguori, Giovanna Polcaro, Francesco Sabbatino, and Stefano Pepe. "Evaluation of Potential Predictive Biomarkers for Defining Brain Radiotherapy Efficacy in Non-Small Cell Lung Cancer Patients with Brain Metastases: A Case Report and a Narrative Review." Clinics and Practice 13, no. 6 (November 30, 2023): 1549–60. http://dx.doi.org/10.3390/clinpract13060136.
Анотація:
Non-small cell lung cancer (NSCLC) is the second most common cancer worldwide, resulting in 1.8 million deaths per year. Most patients are diagnosed with a metastatic disease. Brain metastases are one of the most common metastatic sites and are associated with severe neurological symptoms, shorter survival, and the worst clinical outcomes. Brain radiotherapy and systemic oncological therapies are currently used for controlling both cancer progression and neurological symptoms. Brain radiotherapy includes stereotactic brain ablative radiotherapy (SBRT) or whole brain radiotherapy (WBRT). SBRT is applied for single or multiple (up to ten) small (diameter less than 4 cm) lesions, whereas WBRT is usually applied for multiple (more than ten) and large (diameter greater than 4 cm) brain metastases. In both cases, radiotherapy application may be viewed as an overtreatment which causes severe toxicities without achieving a significant clinical benefit. Thus far, a number of scoring systems to define the potential clinical benefits derived from brain radiotherapy have been proposed. However, most are not well established in clinical practice. In this article, we present a clinical case of a patient with advanced NSCLC carrying a BRAFV600E mutation and brain metastases. We review the variables in addition to applicable scoring systems considered to have potential for predicting clinical outcomes and benefits of brain radiotherapy in patients with advanced NSCLC and brain metastases. Lastly, we highlight the unmet need of specific scoring systems for advanced NSCLC patients with brain metastases carrying oncogene alterations including BRAFV600E mutations.
36
Drilon, Alexander E., Melissa Lynne Johnson, Shirish M. Gadgeel, Dale Nepert, Gang Feng, Marzieh Golmakani, Micaela Reddy, et al. "A first-in-human, phase 1 study of the SHP2 inhibitor PF-07284892 as monotherapy and in combination with different targeted therapies in oncogene-driven, treatment-resistant solid tumors." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 3020. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.3020.
Анотація:
3020 Background: Src homology region 2 domain-containing phosphatase-2 (SHP2) activation mediates targeted therapy resistance in various oncogene-driven cancers. In this phase 1 study (NCT04800822), the novel SHP2 inhibitor PF-07284892 (ARRY-558) was evaluated alone and in combination with different targeted therapies in patients (pts) with oncogene-driven tumors that progressed on prior targeted therapy. Unlike other phase I studies, the unique design of this trial allowed pts to receive combination therapy during dose escalation after a period of PF-07284892 monotherapy. This is critical given that monotherapy efficacy was deemed unlikely based on preclinical data. Methods: Eligible pts with advanced solid tumors were enrolled into escalating dose cohorts of PF-07284892 monotherapy. In the absence of dose limiting toxicity (DLT), matched targeted therapy (lorlatinib for ALK/ROS1 fusion+ cancers, encorafenib + cetuximab for BRAFV600E colorectal cancers, and binimetinib for MAPK-mutant cancers) could be added after 6 weeks of monotherapy at the discretion of the investigator. Primary objectives were safety, tolerability, and recommended dose for further evaluation (RDE) determination. Secondary/exploratory objectives included analyses of pharmacokinetics (PK), circulating tumor DNA (ctDNA), and monotherapy/combination therapy objective response (RECIST v1.1). Results: As of 9/19/2022, 33 pts with oncogene-driven solid tumors were enrolled (20-80 mg, orally twice weekly, day 1 and 4 or day 1 and 2 schedule), of whom 18 received combination therapy (5 ALK/ROS1 fusion+ cancers, 4 BRAFV600E+ CRCs, 9 MAPK mutant cancers). The median age was 54.5 y (range 32-78). The most common treatment-related adverse events (TRAEs; >15%) for monotherapy were anemia (21%), peripheral edema (18%), and increased AST (18%). Cycle 1 monotherapy DLTs occurred in 4 pts: G3 increased AST, ALT, and bilirubin (n=1); anemia (n=1); and increased AST and ALT, and thrombocytopenia (n=1); and G4 bilirubin (n=1). PF-07284892 PK was dose proportional. 40 mg twice weekly (day 1 and 2) was selected as the RDE. With combination therapy, confirmed RECIST v1.1 partial responses (PR) were observed in 3 treatment-refractory pts (2 lorlatinib and 1 binimetinib combination), and stable disease was observed in 6 treatment-refractory pts. ≥80% ctDNA founder mutation reduction was observed post combination therapy initiation in 2 of the responding pts. Conclusions: PF-07284892 was generally well tolerated alone and in combination with rational targeted therapies. This study design enabled combination therapy rescue of disease progression on PF-07284892 monotherapy with 3 pts achieving confirmed PR. Clinical trial information: NCT04800822 .
37
Robb, Ryan, Linlin Yang, Changxian Shen, Adam R. Wolfe, Amy Webb, Xiaoli Zhang, Marall Vedaie, et al. "Inhibiting BRAF Oncogene–Mediated Radioresistance Effectively Radiosensitizes BRAFV600E-Mutant Thyroid Cancer Cells by Constraining DNA Double-Strand Break Repair." Clinical Cancer Research 25, no. 15 (May 16, 2019): 4749–60. http://dx.doi.org/10.1158/1078-0432.ccr-18-3625.
38
Alotaibi, Sultan, Osama Alhafi, Hatem Nasr, Khalid Eltayeb, and Ghaleb Elyamany. "Erdheim-Chester Disease: Case Report with Aggressive Multisystem Manifestations and Review of the Literature." Case Reports in Oncology 10, no. 2 (June 14, 2017): 501–7. http://dx.doi.org/10.1159/000477336.
Анотація:
Erdheim-Chester disease (ECD) is an extremely rare and aggressive form of non-Langerhans cell histiocytosis. ECD usually presents with bone pain in adults aged 40–60. Its etiology is unknown but it is thought to be either a reactive or neoplastic disorder. Recently, mutation of the proto-oncogene BRAF (BRAFV600E) has been found in more than 50% of cases. The multisystemic form of ECD is associated with significant morbidity, which may arise due to histiocytic infiltration of critical organ systems. The common sites of involvement are the skeleton, central nervous system, cardiovascular system, lungs, retroperitoneum, and skin. Current available treatment is interferon alpha as the first line of treatment. Treatment with other agents is based on anecdotal case reports. Cladribine, anakinra, and vemurafenib (BRAF inhibitor) are currently advocated as promising second-line treatments for patients whose response to interferon alpha is unsatisfactory. Herein, we are reporting a middle-aged Saudi male patient with an aggressive type of ECD and highlighting the clinical, radiological, and pathological manifestations associated with ECD and the various treatment options and patient follow-up.
39
Dawar, Richa, Kunal Gawri, Estelamari Rodriguez, Deukwoo Kwon, Fahmin Basher, Philippos Apolinario Costa, Khadeja Khan, Tisdrey Torres, Chukwuemeka Ikpeazu, and Gilberto Lopes. "Clinical attributes and outcomes in metastatic non-small cell lung cancer bearing BRAF mutations treated with targeted therapy versus immunotherapy." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21219-e21219. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21219.
Анотація:
e21219 Background: Mutations in BRAF oncogene have been identified in about 2-4% of non-small cell lung cancer (NSCLC) patients. Combination of tyrosine kinase inhibitors (TKI), dabrafenib and trametinib has shown improved and enduring results in both first line and second line setting. Given the rarity of BRAF mutations, and the approval of TKI, the role of Immune Checkpoint Inhibitors (ICI) still needs to be ascertained. Methods: We conducted a retrospective review of 19 BRAF-mutant lung cancer patients from 2013-2020 at the University of Miami. Clinicopathologic features, and patient’s response to chemotherapy/ICI vs anti-BRAF targeted therapy (ABTT) was investigated. Duration of response (DOR) was calculated from the initiation of therapy, and Overall survival (OS) was calculated from the diagnosis of metastatic disease. OS was estimated by Kaplan-Meier method and log-rank test was used to compare groups. Hazard ratio (HR) and corresponding 95% confidence interval were estimated using Cox proportional hazards regression model. All tests were two sided and statistical significance was considered when p<0.05. Results: Total 19 patients with a median age of 63 (range 54-87) were identified from a cohort of 575 sequenced lung cancer patients (prevalence of 3.3%). 6 patients were never-smokers, 13 former/current smokers; 10 were women; 10 were Non-Hispanic White, 8 Hispanic, and 1 African American. Majority had adenocarcinoma (n=17) and non-V600E BRAF mutation (n=13)). PD-L1 expression testing (n=11) was negative in 55% (n=6 of 11), low in 9% (n=1 of 11), and high in 36% (n=4 of 11). All patients presented with metastatic disease; lung (16), bone (7), brain (5), and liver (4). 47.4% (n=9) of patients received platinum-based doublet chemotherapy as first-line (FL) treatment; 21.1% (n=4) received combined chemotherapy+ICI as FL; 5% (n=1) received ABTT as FL. Overall, 47% (n=9) received ABTT; 11.1% (n=1) as FL, 33.3% (n=3) as second line, 44.4% (n=4) as third line, and 11.1% (n=1) as fourth line. Median OS in the entire cohort was 1.86 years (95 % CI :1.26-2.32). Median DOR to ICI as first line or second line agent was 3 months (mos) (range 0.5-25mos). Median DOR to TKI in BRAFV600E cases was 13 mos (range 7-53mos), as second line agent or beyond. Among patients with BRAFV600E mutation, median OS was 4.89 years (95% CI 4.31-NA) in recipients of ABTT, and 1.68 years (95% CI not estimable) in patients who did not receive ABTT. Conclusions: In our BRAF-mutant NSCLC cohort, median DOR was greater in patients treated with ABTT, than those with ICI. ABTT treated BRAFV600E-mutant patients had longer OS, in comparison to those treated without ABTT. Our analysis highlights a potentially significant benefit of ABTT, and an unsatisfactory response with ICI, in patients harboring BRAFV600E mutation; therefore, the role of ICI in this subgroup needs further investigation.
40
Geisen, Mariah, Josiane weber-Tessmann, Courtney Kelson, Daheng He, Chi Wang, Abu Saleh Mosa Faisal, Jill Kolesar, and Yekaterina Zaytseva. "Abstract 4760: Inhibition of FASN postpones development of resistance to BRAF inhibitors in colorectal cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4760. http://dx.doi.org/10.1158/1538-7445.am2024-4760.
Анотація:
Abstract Introduction: Mutations in proto-oncogene BRAF occur in about 10-15% of CRC patients and BRAFV600E is the most common. For patients who undergo BRAF-targeted therapy, resistance develops 4-6 months after treatment initiation and results in more aggressive disease. We found that development of resistance to BRAF inhibitors (BRAFi) is associated with an increase in lipid metabolism and expression of fatty acid synthase (FASN). FASN is a key enzyme of lipid synthesis overexpressed in CRC. Therefore, our hypothesis is that inhibition lipid metabolism via FASN will postpone development of resistance to BRAFi. Methods: We established CRC cells resistant to PLX8394, a novel BRAFi. To evaluate differences in parental and resistance cells, CellTiterGlo 2.0, PrestoBlue, CytoSelectTM Invasion Assay, Triglyceride Assay, Seahorse XF, and confocal microscopy were used. Combination of PLX8394 and TVB3664 or C75 (FASN inhibitors) was tested on cell viability, colony formation, and synergy studies in parental and BRAFi resistant cells. Results: The development of resistance to BRAFi promotes cellular proliferation and increases cyclin D and survivin expression in vitro and in vivo. BRAFi resistance is also associated with an increase in invasive properties and loss of E-cadherin expression. Metabolic changes include an increase in lipid metabolism, oxidative phosphorylation, and triglycerides storage. RNAseq and western blot analysis show significant upregulation of FASN in BRAFi resistant cells. Using cell viability and soft agar colony formation assays, we show that combined PLX8394 and TVB3664 treatment leads to a significantly higher decrease in cell viability and colony formation as compared to each drug alone in parental cells but not in BRAFi resistant cells. The calculation of a Bliss synergy score confirms that combination treatment with C75 and PLX8394 has synergetic effect in BRAFV600E cells. To further confirm that FASN contributes to resistance to BRAFi, we show that HT29 FASN shRNA cells are more susceptible to PLX8394 treatment as compared to control cells. Importantly, our data show that the long-term treatment with PLX8394 in combination with TVB3664 postpones development of resistance to BRAFi as compared to cells treated with PLX8394 alone. Conclusion: Our study demonstrates that resistance to BRAFi is associated with a significant increase in proliferation, metastasis, and lipid metabolism. We demonstrate that combination of FASN inhibitors and BRAFi postpones development of resistance in BRAFV600E cells. However, FASN inhibition does not sensitize cells to BRAFi in already resistance cells, suggesting that this approach cannot be used to overcome acquired resistance to BRAFi. In summary our data suggest that an addition of TVB3664 at the beginning of BRAF treatment regimen could be an efficacious treatment strategy for BRAFV600E CRC patients. Citation Format: Mariah Geisen, Josiane weber-Tessmann, Courtney Kelson, Daheng He, Chi Wang, Abu Saleh Mosa Faisal, Jill Kolesar, Yekaterina Zaytseva. Inhibition of FASN postpones development of resistance to BRAF inhibitors in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4760.
41
Riesco-Eizaguirre, Garcilaso, Irene Rodríguez, Antonio De la Vieja, Eugenia Costamagna, Nancy Carrasco, Manuel Nistal та Pilar Santisteban. "The BRAFV600E Oncogene Induces Transforming Growth Factor β Secretion Leading to Sodium Iodide Symporter Repression and Increased Malignancy in Thyroid Cancer". Cancer Research 69, № 21 (27 жовтня 2009): 8317–25. http://dx.doi.org/10.1158/0008-5472.can-09-1248.
42
Schott, M. "The BRAFV600E Oncogene Induces Transforming Growth Factor β Secretion Leading to Sodium Iodide Symporter Repression and Increased Malignancy in Thyroid Cancer". Yearbook of Endocrinology 2010 (січень 2010): 154–55. http://dx.doi.org/10.1016/s0084-3741(10)79511-1.
43
Pricl, Sabrina, Erik Laurini, Domenico Marson, and Gabriele Cavalieri. "Abstract C153: Rare BRAF mutations in menlanoma and beyond: Rationalizing the afficacy of B-raf inhibitors via HPC-based in silico/in vitro investigations." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): C153. http://dx.doi.org/10.1158/1535-7163.targ-23-c153.
Анотація:
Abstract Melanoma is a highly aggressive type of cancer that affects the integumentary system and for which a family history of the disease, a fair complexion, the presence of a large number of moles, and skin exposure to natural/artificial ultraviolet (UV) radiation constitute established risk factors for malignancy development. The v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine protein kinase that plays a critical role in the RAS-RAF-MEK-ERK mitogen–activated protein kinase (MAPK) cell signaling pathway. Despite over 20 years of research into the regulation and function of the RAF proteins, it was only relatively recently that the BRAF isoform is mutated at a high frequency in different human cancers, identifying this kinase as another important oncogene along this pathway. FFocusing on melanoma, activating BRAF mutations were identified in 37%−53% of patients with the malignant form of this pathology, the most prevalent, missense kinase alteration being the replacement of the small, apolar residue valine (V) with the negatively-charged, phosphorylation mimicking glutamic acid (E) at position 600 (BRAFV600E) within the protein catalytic (i.e., ATP binding) site. It is interesting to note that BRAFV600E is not a UV-driven mutation; in fact, it may also be found in the molecular profile of atypical benign nevi; moreover, although BRAFV600E is the most frequent mutation (accounting for nearly 40% of all melanomas and in approximately 90% of BRAF-mutant melanomas), other more or less frequent activating variants in BRAF have also been reported, which include other aminoacidic substitutions at the same position (e.g., V600K/D/R), G469A/V/S, L597Q/R/S/V, A598V, and K601E/N/T, among others. Importantly, these mutations are also found in other cancers, e.g., thyroid cancer, colorectal cancer, and some brain malignancies including glioblastoma, pilocytic astrocytoma, and pediatric low-grade glioma. In this multidisciplinary work, we focused on some of these rare BRAF variants and studied their ability to interact with several, first-line FDA approved BRAF initbitors (BRAFis) from a structural, chemico-phisical and in vitro perspectives. To the purpose, we employed a combitation of in silico techniques, based on the use of high-performance computing (HPC), chemico-physical and spectroscopical techniques, and in vitro tests to verify the interactions between these mutated BRAF isoforms with the inhibitors. As a main point, we were able to determine the binding thermodinamics and kinetics of the selected BRAFis to the mutant BRAF proteins, and each BRAF/drug complex was characterized from a structural standpoint. All these information ultimately revelaed that some of the BRAF isoforms are able to effectively bind the corresponding BRAi, with consequent switch-off of the signaling patwhay, at least in vitro. The presented mutlidisciplinary protocol could be adoped in the future to predict the response of newly discovered BARF variants and/or variants of unknown significance towards current or newly-designed BRAFis. Citation Format: Sabrina Pricl, Erik Laurini, Domenico Marson, Gabriele Cavalieri. Rare BRAF mutations in menlanoma and beyond: Rationalizing the afficacy of B-raf inhibitors via HPC-based in silico/in vitro investigations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C153.
44
Lim, Kee Siang, Zachary Wei Ern Yong, Huajing Wang, Tuan Zea Tan, Ruby Yun-Ju Huang, Daisuke Yamamoto, Noriyuki Inaki, et al. "Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells." Journal of Biological Chemistry 295, no. 19 (March 24, 2020): 6387–400. http://dx.doi.org/10.1074/jbc.ra120.012943.
Анотація:
The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.
45
Chan, Lai N., Christian Hurtz, Huimin Geng, Franziska Auer, Zhengshan Chen, Gang Xiao, Jae-Woong Lee, Kadriye Nehir Cosgun, B. Hilda Ye, and Markus Muschen. "Ras-Driven B-Cell Transformation Targets Developmental Rewiring of Cytokine to Pre-B Cell Receptor Signaling." Blood 132, Supplement 1 (November 29, 2018): 1336. http://dx.doi.org/10.1182/blood-2018-99-115514.
Анотація:
Abstract Ras-pathway lesions are oncogenic drivers in ~45% of B-cell acute lymphoblastic leukemia (B-ALL) cases. Activating mutations of NRAS and KRAS are oncogenic drivers in B-ALL while the BRAFV600E mutation occurs in almost all cases of B-cell hairy cell leukemia. Less frequent lesions resulting in increased ERK-signaling in B-cell malignancies include activating mutations of RAF1, MAP2K1 and the PTPN11 phosphatase as well as deleterious mutations of the Ras-GTPase activator NF1. Interestingly, increased immunoglobulin light chain gene expression was observed in B-ALL cases with RAS-pathway lesions (COG P9906), reflecting engagement of pre-B cell receptor (pre-BCR) downstream signaling. Here we tested the hypothesis that oncogenic RAS-signaling in B-ALL mimics pre-BCR-induced developmental rewiring of signal transduction at the pro-B to pre-B cell transition and identified PTPN6 and BCL6 as therapeutic targets in RAS-driven B-ALL. During early B-cell development, pro-B cells transition from cytokine- to pre-B cell receptor (pre-BCR)-dependent survival and proliferation signals. Inducible activation of immunoglobulin (Ig) µ heavy chain (µHC) expression induced developmental progression and surface expression of Ig κ light chains. Notably, inducible activation of oncogenic NRASG12D had the same effect and resulted in increased surface expression of Ig κ light chains. Furthermore, studying genetic models for this transition revealed that both pre-BCR signaling and RAS-oncogenes suppressed cytokine receptor/STAT5-signaling and induced massive de novo expression of the proto-oncogene and transcriptional repressor BCL6. Our genetic studies revealed that the SH2-domain containing protein tyrosine phosphatase PTPN6 was activated by oncogenic RAS-signaling and essential for the switch from STAT5 to BCL6-activation. Given that oncogenic RAS activated PTPN6, we tested the role of PTPN6 in RAS-driven leukemogenesis. To this end, ablation of Ptpn6 in NRASG12D-driven B-ALL resulted in depletion of cells from cell culture in competitive-growth assays and reduced the number of colonies formed in semi-solid methylcellulose. Collectively, these findings suggest that PTPN6 represents a potential therapeutic intervention point in RAS-driven B-ALL. In addition to PTPN6, we investigated the role of BCL6 in RAS-driven B-ALL. Aberrant activation of oncogenic RAS results in oncogene-induced senescence (OIS) characterized by induction of ARF/p53 and irreversible cell cycle arrest in the G1 phase. For oncogenic Ras-signaling, BCL6 was required to oppose ERK-mediated activation of p21, p27 and p53 checkpoint molecules in B-ALL. Here we tested the hypothesis that BCL6 bypasses the RAS-mediated OIS program to facilitate transformation. To this end, increases in number of colonies formed in semi-solid methylcellulose were observed upon inducible activation of Bcl6 in NRASG12D B-ALL cells. Furthermore, loss of Bcl6 function in NRASG12D B-ALL cells resulted in depletion of cells from cell culture in competitive growth assays and reduced colony forming ability. Importantly, expression of NRASG12D in Bcl6+/+ pre-B cells resulted in transformation and fatal leukemia in transplant recipient mice. In striking contrast, Bcl6-/- pre-B cells transduced with NRASG12D failed to initiate fatal disease in vivo. Furthermore, pharmacological inhibition of BCL6 restored sensitivity to chemotherapy in patient-derived KRASG12V B-ALL cells. In conclusion, we identified oncogenic RAS-signaling as functional mimics of pre-BCR signaling. Oncogenic RAS induced expression of BCL6 at the expense of cytokine receptor/STAT5-signaling. Our genetic studies identified PTPN6 as a critical effector molecule of the switch from cytokine receptor to pre-BCR signaling. Importantly, we identified PTPN6 and BCL6 as potential therapeutic intervention points in RAS-driven B-ALL. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
46
Liebig, Janika K., Silke Kuphal, and Anja Katrin Bosserhoff. "HuRdling Senescence: HuR Breaks BRAF-Induced Senescence in Melanocytes and Supports Melanoma Growth." Cancers 12, no. 5 (May 21, 2020): 1299. http://dx.doi.org/10.3390/cancers12051299.
Анотація:
In addition to genetic changes, post-transcriptional events strongly contribute to the progression of malignant tumors. The RNA-binding protein HuR (ELAVL1) is able to bind and stabilize a large group of target mRNAs, which contain AU-rich elements (ARE) in their 3′-untranslated region. We found HuR to be upregulated in malignant melanoma in vitro and in vivo, significantly correlating with progression in vivo. Additionally, we could show that miR-194-5p can regulate HuR expression level. HuR knockdown in melanoma cells led to the suppression of proliferation and the induction of cellular senescence. Interestingly, HuR overexpression was sufficient to inhibit senescence in BRAFV600E-expressing melanocytes and to force their growth. Here, MITF (Microphthalmia-associated transcription factor), a key player in suppressing senescence and an ARE containing transcript, is positively regulated by HuR. Our results show for the first time that the overexpression of HuR is an important part of the regulatory pathway in the development of malignant melanoma and functions as a switch to overcome oncogene-induced senescence and to support melanoma formation. These newly defined alterations may provide possibilities for innovative therapeutic approaches.
47
Kunz, Manfred, and Julio Vera. "Modelling of Protein Kinase Signaling Pathways in Melanoma and Other Cancers." Cancers 11, no. 4 (April 3, 2019): 465. http://dx.doi.org/10.3390/cancers11040465.
Анотація:
Melanoma is a highly aggressive tumor with a strong dependence on intracellular signaling pathways. Almost half of all melanomas are driven by mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) with BRAFV600E being the most prevalent mutation. Recently developed targeted treatment directed against mutant BRAF and downstream mitogen-activated protein kinase (MAPK) MAP2K1 (also termed MEK1) have improved overall survival of melanoma patients. However, the MAPK signaling pathway is far more complex than a single chain of consecutively activated MAPK enzymes and it contains nested-, inherent feedback mechanisms, crosstalk with other signaling pathways, epigenetic regulatory mechanisms, and interacting small non-coding RNAs. A more complete understanding of this pathway is needed to better understand melanoma development and mechanisms of treatment resistance. Network reconstruction, analysis, and modelling under the systems biology paradigm have been used recently in different malignant tumors including melanoma to analyze and integrate ‘omics’ data, formulate mechanistic hypotheses on tumorigenesis, assess and personalize anticancer therapy, and propose new drug targets. Here we review the current knowledge of network modelling approaches in cancer with a special emphasis on melanoma.
48
Groisberg, Roman, David S. Hong, Filip Janku, Yunfang Jiang, ChongJuan Wei, Daniel D. Karp, Apostolia Maria Tsimberidou, et al. "SWI/SNF complex subunit aberrations in diverse cancers: Next-generation sequencing of 539 patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 2588. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.2588.
Анотація:
2588 Background: The SWI/SNF complex is an ATP-dependent chromatin remodeler that is enriched at promoters and enhancers of active genes. It has been implicated as both an oncogene and tumor suppressor. Specific subunit mutations have even been associated with specific cancers with increased PRC2 component EZH2 activity. EZH2/ EED inhibitors are in early stage development to target SWI/SNF complex. Methods: We analyzed 539 consecutive patients with diverse malignancies who were referred for Phase 1 clinical trials and had CLIA certified targeted next-generation sequencing (Foundation one) for presence of aberrations in SWI/SNF complex genes (ARID1A, ARID2, PBRM1, SMARCA4, SMARCB1). Patient charts were reviewed for general demographics (sex, age at diagnosis and death, performance status), tumor histology, stage, metastatic sites, treatment history, outcomes and co-occurring alterations. Results: Fifty patients had mutations in SWI/SNF subunits. Median age at diagnosis was 56 (14-79 years) and M:F ratio 21:29. Kidney, colorectal, ovary and breast were the most common among 15 different cancers. Most were stage IV at diagnosis (68%), had a strong family history of cancer (80%) & were smokers (42%). The most common mutated subunit was ARID1A (50%) followed by PBRM1 (16%), ARID2 (12%), SMARCA4 (12%), and SMARCB1 (10%). All mutations were predicted to be inactivating. Actionable co-occurring pathway alterations were found in 58% of patients, most commonly PI3K (26%), FGFR(16%), and NOTCH1/2 (10%). The majority of patients (62%) were enrolled on a clinical trial. Best responses on other targeted agents included 1 CR (BRAFV600E colon), 4 PR (transformed teratoma, skin SCC, ovarian, NSCLC), 12 SD. Exceptional responders included BRAFV600E colon cancer on BRAFi based therapy for 66 cycles, NSCLC on Nivolumab for 34 cycles, and MSI-H colon cancer on regorafenib/cetuximab for 27 cycles. Conclusions: The role of SWI/SNF in patients with extended clinical benefit from other targeted agents should be explored. Co-occurring genetic alterations are observed in PI3K, FGFR, and NOTCH pathways. Future pre-clinical and/or clinical studies could target these pathways in combination with EZH2/EED inhibitors.
49
Borgenvik, Anna, Sean Misek, Alexander Zhang, Ruth Fekade, Timothy Ragnoni, Aaron Fultineer, Kevin Zhou, et al. "LGG-29. BEYOND MAPK SIGNALING - GENOME-SCALE CRISPR/CAS9 SCREENS REVEAL NEW TARGETS FOR TREATMENT OF KIAA1549::BRAF-DRIVEN PEDIATRIC LOW-GRADE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.422.
Анотація:
Abstract Since the KIAA1549::BRAF fusion was discovered as the most common driver of pediatric low-grade glioma (pLGG), it has been hypothesized that the fusion induces oncogenicity through BRAF activation as a result of KIAA1549 replacing the BRAF negative regulatory N-terminus. This led to the rapid translation of MAPK pathway inhibitors into the clinical setting. Despite most tumors exhibiting promising initial responses, some tumors are not sensitive and about half of responsive tumors grow back after treatment cessation. Therefore, strategies that result in sustained tumor responses are desperately needed. We have recently performed genome-scale CRISPR/Cas9 screens across isogenic neural stem cell models transduced to express pLGG-associated oncogenes (KIAA1549::BRAF, BRAFV600E, and multiple FGFR1 and MYB family alterations) to generate a dependency map of genetic vulnerabilities associated with expression of these oncogenes. We also included normal neural stem cells to allow identification of genetic dependencies specifically induced by the expression of each oncogene. Surprisingly, through these efforts, we have discovered KIAA1549::BRAF expressing cells to harbor striking and specific dependency on multiple members of an enzymatic complex that exerts its activity outside of the MAPK signaling axis*. Interestingly, this enzymatic complex has been described to modify only a few substrates, including KIAA1549, suggesting specificity. We have now validated this dependency across other isogenic models of KIAA1549::BRAF-expressing cells. Finally, our KIAA1549::BRAF-expressing models exhibit preferential sensitivity to a tool compound that targets our novel enzyme, suggesting novel therapeutic potential for KIAA1549::BRAF. These findings highlight a MAPK pathway-independent avenue for therapeutically targeting the most frequent genomic alterations in pediatric brain tumors. Consequently, we also propose that the fusion partner KIAA1549 is instrumental for the aberrant BRAF signaling driving pLGGs. (* we are currently in the process of working with our IP offices to ensure that we can disclose the names of the genes and proteins at the ISPNO meeting)
50
Lee, Joon-Hyop, Jiyoung Ahn, Won Seo Park, Eun Kyung Choe, Eunyoung Kim, Rumi Shin, Seung Chul Heo, et al. "Colorectal Cancer Prognosis is Not Associated with BRAF and KRAS Mutations-A STROBE Compliant Study." Journal of Clinical Medicine 8, no. 1 (January 17, 2019): 111. http://dx.doi.org/10.3390/jcm8010111.
Анотація:
Background: We investigated the associations between v-Raf murine sarcoma viral oncogene homolog B1 (BRAFV600E, henceforth BRAF) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and colorectal cancer (CRC) prognosis, using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GSE39582) datasets. Materials and Methods: The effects of BRAF and KRAS mutations on overall survival (OS) and disease-free survival (DFS) of CRC were evaluated. Results: The mutational status of BRAF and KRAS genes was not associated with overall survival (OS) or DFS of the CRC patients drawn from the TCGA database. The 3-year OS and DFS rates of the BRAF mutation (+) vs. mutation (−) groups were 92.6% vs. 90.4% and 79.7% vs. 68.4%, respectively. The 3-year OS and DFS rates of the KRAS mutation (+) vs. mutation (−) groups were 90.4% vs. 90.5% and 65.3% vs. 73.5%, respectively. In stage II patients, however, the 3-year OS rate was lower in the BRAF mutation (+) group than in the mutation (−) group (85.5% vs. 97.7%, p <0.001). The mutational status of BRAF genes of 497 CRC patients drawn from the GSE39582 database was not associated with OS or DFS. The 3-year OS and DFS rates of BRAF mutation (+) vs. mutation (−) groups were 75.7% vs. 78.9% and 73.6% vs. 71.1%, respectively. However, KRAS mutational status had an effect on 3-year OS rate (71.9% mutation (+) vs. 83% mutation (−), p = 0.05) and DFS rate (66.3% mutation (+) vs. 74.6% mutation (−), p = 0.013). Conclusions: We found no consistent association between the mutational status of BRAF nor KRAS and the OS and DFS of CRC patients from the TCGA and GSE39582 databases. Studies with longer-term records and larger patient numbers may be necessary to expound the influence of BRAF and KRAS mutations on the outcomes of CRC.