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Rugerio-Martínez, Claudia Ivette, Daniel Ramos, Abel Segura-Olvera, Nadia Mireya Murillo-Melo, Yessica Sarai Tapia-Guerrero, Raúl Argüello-García, Norberto Leyva-García, Oscar Hernández-Hernández, Bulmaro Cisneros, and Rocío Suárez-Sánchez. "Dp71 Point Mutations Induce Protein Aggregation, Loss of Nuclear Lamina Integrity and Impaired Braf35 and Ibraf Function in Neuronal Cells." International Journal of Molecular Sciences 23, no. 19 (October 6, 2022): 11876. http://dx.doi.org/10.3390/ijms231911876.
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Dystrophin Dp71 is the most abundant product of the Duchenne muscular dystrophy gene in the nervous system, and mutations impairing its function have been associated with the neurodevelopmental symptoms present in a third of DMD patients. Dp71 is required for the clustering of neurotransmitter receptors and the neuronal differentiation of cultured cells; nonetheless, its precise role in neuronal cells remains to be poorly understood. In this study, we analyzed the effect of two pathogenic DMD gene point mutations on the Dp71 function in neurons. We engineered C272Y and E299del mutations to express GFP-tagged Dp71 protein variants in N1E-115 and SH-SY5Y neuronal cells. Unexpectedly, the ectopic expression of Dp71 mutants resulted in protein aggregation, which may be mechanistically caused by the effect of the mutations on Dp71 structure, as predicted by protein modeling and molecular dynamics simulations. Interestingly, Dp71 mutant variants acquired a dominant negative function that, in turn, dramatically impaired the distribution of different Dp71 protein partners, including β-dystroglycan, nuclear lamins A/C and B1, the high-mobility group (HMG)-containing protein (BRAF35) and the BRAF35-family-member inhibitor of BRAF35 (iBRAF). Further analysis of Dp71 mutants provided evidence showing a role for Dp71 in modulating both heterochromatin marker H3K9me2 organization and the neuronal genes’ expression, via its interaction with iBRAF and BRAF5.
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Mi LEE, Young, and Wankee KIM. "Association of human kinesin superfamily protein member 4 with BRCA2-associated factor 35." Biochemical Journal 374, no. 2 (September 1, 2003): 497–503. http://dx.doi.org/10.1042/bj20030452.
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A large portion of human kinesin superfamily protein member 4 (KIF4) is associated with the nuclear matrix during the interphase, while a small portion is found in the cytoplasm. During mitosis, it is associated with chromosomes throughout the entire process. In the present study, we identified a protein that interacts with KIF4 using a yeast two-hybrid system, co-immunoprecipitation and co-fractionation. This protein is BRCA2-associated factor 35 (BRAF35) containing a non-specific DNA binding high-mobility-group domain and a kinesin-like coiled-coil domain. It appeared that the interaction between the two proteins occurs through their respective α-helical coiled-coil domains. The co-fractionation experiment revealed that KIF4 and BRAF35 were present in a complex of approx. 540 kDa. The composition and biological significance of this complex should be studied further.
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Hakimi, M. A., D. A. Bochar, J. Chenoweth, W. S. Lane, G. Mandel, and R. Shiekhattar. "A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes." Proceedings of the National Academy of Sciences 99, no. 11 (May 28, 2002): 7420–25. http://dx.doi.org/10.1073/pnas.112008599.
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Zanchetta, Melania E., Luisa M. R. Napolitano, Danilo Maddalo, and Germana Meroni. "The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1864, no. 10 (October 2017): 1844–54. http://dx.doi.org/10.1016/j.bbamcr.2017.07.014.
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Ceballos-Chavez, M., S. Rivero, P. Garcia-Gutierrez, M. Rodriguez-Paredes, M. Garcia-Dominguez, S. Bhattacharya, and J. C. Reyes. "Control of neuronal differentiation by sumoylation of BRAF35, a subunit of the LSD1-CoREST histone demethylase complex." Proceedings of the National Academy of Sciences 109, no. 21 (May 8, 2012): 8085–90. http://dx.doi.org/10.1073/pnas.1121522109.
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Lee, Belinda, Angelyn Anton, Margaret Lee, Rachel Wong, Phillip Parente, Jeremy David Shapiro, Desmond Yip, et al. "Examining progression-free survival in first- and second-line treatment for BRAF-mutant metastatic colorectal cancer (CRC)." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 728. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.728.
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728 Background: BRAF mutated (BRAFm) CRC represents ~10% of all CRC and is associated with significantly poorer prognosis. However, responses to chemotherapy do still occur. Some data suggest that the poor prognosis associated with BRAFm CRC is dominated by substantially poorer second line PFS (PFS2), whereas first line PFS (PFS1) was similar for both BRAFm and BRAF wildtype (BRAFwt) CRC. Using a large multicenter dataset, our study aimed to examine PFS1 and PFS2 in BRAFm versus BRAFwt CRC. Methods: Prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) database was interrogated. PFS was calculated and compared in patients with BRAFm versus BRAFwt CRC. Median survival was determined by the Kaplan-Meier method and compared using the log rank test. Results: TRACC identified 523 CRC patients with known BRAF mutation status, who received first-line chemotherapy: 53 (10%) were BRAFm, while 470 (90%) were BRAFwt. At the time of data analysis, only 231 (44%) CRC patients had received second-line chemotherapy, of which 21 (9%) were BRAFm and 210 (91%) were BRAFwt. PFS1 analyses demonstrated significantly poorer survival in the BRAFm population (Median 7.8mo versus 11.5mo, HR 1.72, p = 0.0026). PFS2 analyses revealed similar findings for the BRAFm population, albeit non-significant due to smaller numbers (Median 5.5mo versus 7.7mo, HR1.26, p = 0.44). Conclusions: Our study demonstrated that BRAFm CRC was associated with poorer PFS in both first- and second-line settings. Additional analyses will be performed to examine the impact of different treatment strategies and other clinicopathological features.
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Osterlund, Pia J., Emerik Osterlund, Aki Uutela, Päivi Halonen, Raija S. Kallio, Annika Ålgars, Tapio Salminen, et al. "Resectability, conversion and resections rates, and outcomes in RAS&BRAF wildtype (wt), RAS mutant (mt) and BRAFmt metastatic colorectal cancer (mCRC) subgroups in the prospective Finnish RAXO-study." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3532. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3532.
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3532 Background: Outcomes of metastasectomy varies with RAS and BRAF-status, but the effect on resectability, conversion and resection rates has not been extensively studied. Methods: The prospective Finnish RAXO study (NCT01531621) included 1086 patients 2011-2018 (Osterlund et al TLRHE 2021, Isoniemi et al BJS 2021) of which 906 were included in this secondary endpoint analysis. Excluded had missing KRAS/ NRAS/ BRAF-V600E test, were untreatable or had an atypical BRAF mutation. We studied repeated centralized resectability assessment, conversion and resectability rates in mCRC, and overall survival (OS) after resection and/or local ablative therapy (LAT) and systemic therapy. Results: Included were 289 RAS& BRAFwt, 529 RASmt (overrepresented) and 88 BRAFmt, with median age 65.8/66.1/66.9 years. Demographics per RAS& BRAFwt, RASmt and BRAFmt showed significant differences in male proportion (68/61/39%), ECOG PS 2-3 groups (16/14/25%), primary tumour location (right colon 16/30/69%, left colon 47/34/17%, rectum 38/36/14%), but not for Charlson comorbidity index, BMI, resection of primary, synchronous presentation or adjuvant therapy (Bonferroni corrected Chi-square). Metastatic profile was different for liver (78/74/61% per RAS& BRAFwt, RASmt and BRAFmt), lung (24/35/28%) and peritoneal (15/15/32%) metastases, but not for lymph nodes or other sites, nor for number of metastatic sites (1 in 53/54/52%). Upfront resectability rates were different with 32/29/15% for RAS& BRAFwt, RASmt and BRAFmt, respectively, as were conversion rates with 16/13/7%, and resection/LAT rates with 45/37/17%, respectively. Kaplan-Meier median OS estimate in R0/1/2-resected and/or LAT group (n = 342) was 83/69/30 months for RAS& BRAFwt, RASmt and BRAFmt groups, respectively and 5-year OS-rates 67/60/24%, with Cox HR ref/1.53 (95% CI 1.04-2.25)/3.11 (1.49-6.49). In the “systemic therapy only” (n = 564) OS was 29/21/15 months and 5-year OS-rates 11/6/2% respectively, with HR ref/1.43 (1.15-1.76)/2.34 (1.73-3.17). Resection/LAT patients had improved OS over “systemic therapy only” patients in all subgroups, HR 5.74 (3.90-8.44)/5.06 (3.92-6.55)/2.89 (1.43-5.86). Conclusions: There were significant differences in resectability, conversion and resection/LAT rates according to RAS& BRAFwt, RASmt and BRAFmt status. OS was also significantly longer for RAS& BRAFwt versus either mutant. Resected/LAT had better OS than “systemic therapy alone” patients in all subgroups. Clinical trial information: NCT01531621.
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Braithwaite, Matthew, Christopher Duane Nevala-Plagemann, Kelsey Baron, Benjamin Haaland, Lisa M. Pappas, and Ignacio Garrido-Laguna. "Real-world outcomes of patients with BRAF-mutated mCRC treated in the United States." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 4030. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4030.
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4030 Background: BRAF mutations portend a poor prognosis in metastatic colorectal cancer (mCRC). Recent trials have hypothesized that using more aggressive triplet-based chemotherapy regimens such as FOLFOXIRI in the frontline setting may improve outcomes in this patient population. In this study, we utilized real-world data to assess whether FOLFOXIRI is being used in the United States (US) and compared survival outcomes in BRAF mutated (BRAFmt) mCRC stratified by first line (1L) therapy. Methods: The nationwide Flatiron Health EHR-derived de-identified database was reviewed for patients diagnosed with mCRC between 2013 and 2018. Patients who had documented BRAF mutation testing and received a standard 1L therapy were included for analysis. Patients who did not have a visit or medication order within 90 days of metastatic diagnosis were excluded to ensure patients were engaged with care at the data-providing institution. Kaplan-Meier and Cox proportional hazard modeling were used to compare survival outcomes stratified by BRAF mutation status and 1L therapy received. Results: A total of 4,454 patients with documented BRAF mutational status were included, of which 3,988 (89.5%) were BRAF wild type (BRAFwt) and 466 (10.5%) were BRAFmt. Median OS was 15.4 months (mo) in the BRAFmt group compared to 28.1 mo in the BRAFwt group (HR 0.48, 95% CI 0.41- 0.56, p < 0.001). Only 3% (n = 16) of BRAFmt patients received 1L FOLFOXIRI +/- bevacizumab with a median OS of 13.8 mo compared to 15.5 mo in patients receiving a chemotherapy doublet (FOLFOX, CAPEOX, or FOLFIRI) +/- bevacizumab (95% CI 4.9 – not reached vs 14.3 – 19.0, p = 0.38). In BRAFmt patients, multivariate analysis (MVA) did not detect a significant improvement in OS with the use of FOLFIRI plus bevacizumab (HR 0.88, 95% CI 0.50-1.56, p = 0.67) or FOLFOX/CAPEOX plus bevacizumab (HR 0.89, 95% CI 0.59 – 1.34, p = 0.58) when compared to chemotherapy doublet alone. A MVA comparing 1L therapies in the BRAFwt group did not detect a significant improvement in OS with bevacizumab plus chemotherapy doublet compared to chemotherapy doublet alone. When stratified by 1L treatment regimen, similar proportions of BRAFmt patients received second line therapy. Conclusions: This analysis of real-world data confirms the negative prognostic impact of BRAF mutations in mCRC and suggests that FOLFOXIRI has not been widely adopted in the management of these patients in the US. We were unable to demonstrate any significant difference in OS of patients with BRAFmt mCRC based on type of 1L therapy received.
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Hernandez-Aya, Leonel Fernando, Matthew Burke, Jenna M. Collins, Dennis Earle, Melissa Hamilton, Beth L. Nordstrom, Ying Zhang, and Shivani Srivastava. "Real-world treatment patterns and clinical outcomes of advanced melanoma patients following disease progression on anti-PD-1-based therapy." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e22036-e22036. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e22036.
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e22036 Background: Despite the success of anti-programmed cell death-1 (PD-1) based therapies that prolong survival in advanced melanoma, some patients experience disease progression. Real-world treatment patterns and outcomes after progression on anti-PD-1 based regimens are unknown. Methods: Adults with advanced melanoma and a record of disease progression on anti-PD-1 treatment (alone or in combination) between 1 Sept 2014–31 Jan 2019 were selected from the Flatiron Health Oncology electronic medical record (EMR) database for this retrospective study. Index progression date was defined as an event where the treating clinician concluded in the patient record that there had been disease progression. The first subsequent therapy received was identified. Kaplan-Meier methods estimated overall survival (OS) with 95% confidence interval (CI) after the progression date. Analyses were run separately for BRAF mutant (mt) and wild type (wt). Results: Among 2,169 patients with advanced melanoma treated with an anti-PD-1, 213 BRAFmt and 302 BRAFwt had a record of progression following anti-PD-1 initiation and were included; an additional 82 BRAFmt and 138 BRAFwt were excluded due to death without a record of progression. Median age was 64 and 71 years, respectively; 27.7% and 9.9% had >1 line of therapy prior to the anti-PD-1. Among the BRAFmt patients who progressed on anti-PD-1, 94 (44.1%) received no subsequent therapy, 80 (37.6%) BRAF±MEK (± IO), and 16 (7.5%) anti-CTLA4 alone or with anti-PD-1 after progression on the initial anti-PD-1; 11% received other treatments with no clear pattern of care. Median (95% CI) OS from the index progression date for BRAFmt was 11.9 (8.2–16.9) months. In a subgroup of these BRAFmt patients with BRAF treatment prior to or during the first anti-PD-1 line (N = 65), 52.3% had no subsequent therapy and a median OS of 4.0 (2.7–7.5) months. Among the BRAFwt patients who progressed on anti-PD-1, 186 (61.6%) received no subsequent therapy, 46 (15.2%) received anti-CTLA4 alone or with anti-PD-1, 26 (8.6%) switched anti-PD-1s, and 15% received other treatments. Median (95% CI) OS for BRAFwt was 10.1 (8.8–12.5) months. Conclusions: In this real-world retrospective study, > 40% of BRAFmt and > 60% of BRAFwt patients did not initiate a new regimen after progression on anti-PD-1 therapy. Median OS after progression was < 1 year. This may be overestimated, as it excluded patients who died before progression was recorded in the EMR. These findings highlight a need for more effective treatments for advanced melanoma.
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Trunk, Andrew, Matthew Braithwaite, Christopher Nevala-Plagemann, Lisa Pappas, Benjamin Haaland, and Ignacio Garrido-Laguna. "Real-World Outcomes of Patients With BRAF-Mutated Metastatic Colorectal Cancer Treated in the United States." Journal of the National Comprehensive Cancer Network 20, no. 2 (February 2022): 144–50. http://dx.doi.org/10.6004/jnccn.2021.7059.
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Background: BRAF mutations portend a poor prognosis in metastatic colorectal cancer (mCRC). Whether these patients may benefit from more aggressive frontline chemotherapy with a triplet regimen such as FOLFOXIRI remains unclear. We used real-world data from a cohort of patients in the United States to assess the BRAF testing rate, determine the prevalence of FOLFOXIRI use, and compare survival outcomes in mCRC, stratified by BRAF mutation status and first-line therapy. Methods: A nationwide electronic health record–derived deidentified database was reviewed for patients diagnosed with mCRC between 2013 and 2018. Those with documented BRAF mutation testing who received standard first-line therapy were included. Kaplan-Meier estimates with corresponding log-rank tests and Cox proportional hazards modeling compared survival outcomes stratified by BRAF status and first-line therapy. Results: Of 4,457 included patients, 3,991 (89.5%) had BRAF wild-type (BRAFwt) and 466 (10.5%) had BRAF-mutated (BRAFmt) mCRC. Median overall survival (OS) was 15.4 months in the BRAFmt group versus 28.1 months in the BRAFwt group (hazard ratio [HR], 0.48; 95% CI, 0.41–0.56; P<.001). Only 3% of patients with BRAF mutations received first-line FOLFOXIRI ± bevacizumab, with a median OS of 13.8 months compared with 15.5 months in those treated with doublet chemotherapy ± bevacizumab (P=.38). In patients with BRAF mutations, propensity-weighted analysis did not detect a significant improvement in OS with FOLFIRI + bevacizumab (HR, 0.90; 95% CI, 0.58–1.39; P=.63) or FOLFOX/CAPEOX + bevacizumab (HR, 0.81; 95% CI, 0.52–1.26; P=.35) versus doublet chemotherapy alone. In 2018, only 56% of patients diagnosed with mCRC had documented BRAF testing at any time. Conclusions: This real-world data analysis confirms the negative prognostic impact of BRAF mutations in mCRC and suggests that FOLFOXIRI has not been widely adopted in the United States. The proportion of patients with documented BRAF testing in this real-world population was low at 56%. We were unable to show any significant difference in OS of patients with BRAFmt mCRC based on the first-line therapy received.
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Nordstrom, Beth L., Melissa Hamilton, Jenna M. Collins, Dennis Earle, Ying Zhang, Shivani Srivastava, and Leonel Hernandez-Aya. "Treatment patterns and outcomes following disease progression on anti-PD-1 therapies for advanced melanoma." Future Oncology 18, no. 11 (April 2022): 1343–55. http://dx.doi.org/10.2217/fon-2021-0340.
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Background: Anti-PD-1-based therapies prolong survival in advanced melanoma, but disease progression is common. This study evaluated treatment patterns and overall survival (OS) after anti-PD-1 progression. Methods: Retrospective data from patients with advanced melanoma and progression on anti-PD-1 treatment between 2014 and 2019 were taken from Flatiron Health, which reflects largely community practice. Treatment patterns and OS were analyzed for BRAF mutant (mt) and wild-type (wt) subgroups; OS was also examined across all patients. Results: Progression following anti-PD-1 was recorded for 679 patients. Median OS ranged from 5.0 to 11.3 months. Of 275 BRAFmt and 374 BRAFwt patients, 113 (41.1%) and 228 (61.0%) received no subsequent therapy, respectively. However, 48.4% of BRAFmt and 57.8% of BRAFwt patients continued anti-PD-1 treatment beyond progression. Conclusion: This real-world study underscores the need for effective treatments for advanced melanoma post-progression on anti-PD-1 therapy.
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Vergidis, Joanna, Richard John Klasa, Youwen Zhou, Elena Moon, Debbie Jepson, and Kerry J. Savage. "Outcome and prognostic factors in BRAF mutation positive metastatic melanoma treated with a BRAF inhibitor: A population-based study in British Columbia." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e20045-e20045. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e20045.
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e20045 Background: BRAF mutations are present in approximately 40-60% of cutaneous melanomas. The BRAF inhibitor vemurafenib has demonstrated dramatic anti-tumour activity in phase III trials in BRAF mutation positive (BRAFm) metastatic/unresectable melanoma; however, there is limited data outside of clinical trials. Methods: All patients > 18 years of age, PS 0-2, with metastatic/unresectable melanoma considered for treatment with vemurafenib in British Columbia between March 2011 to December 2012 were identified. CNS disease, if present, had to be radiographically stable/asymptomatic and treated with radiation and/or surgery. The BRAF V600E mutation status was evaluated centrally on primary or metastatic biopsies using a real-time PCR assay (Cobas 4800 BRAF Mutation Test, Roche Molecular Systems). Vemurafenib was initially provided through an Expanded Access Program/Roche patient assistance program and subsequently through provincial funding. Results: In total, 84 patients were identified that had undergone BRAF mutation screening, 49(58%) were BRAFm, 35(42%) were BRAFwt. For the BRAFm patients 33 have received 1 cycle of vemurafenib and are included in the present analysis (n=21 (64%) 1st line therapy; 12(36%) > 1st line therapy). BRAFm patients: median age 53 y; 64% male; PS 0/1 76%; LDH elevated 51.5%; M1c 91%; 27% history CNS metastases. With a median follow-up of 4.9 m the median PFS, measured from the 1st dose of vemurafenib, was 9 m and the median OS was 12.4 m. The 1 year PFS and OS were 47% and 50%, respectively. The median OS of patients who progressed following vemurafenib was only 2 months. There was an inferior PFS in patients with an elevated LDH (median PFS 5 m vs not reached, p=0.024) prior to receiving vemurafenib. Conclusions: The efficacy of vemurafenibin BRAF + melanoma in this population-based analysis compares favorably to estimates in the clinical trial setting. The survival of patients who progress on vemurafenib is short, highlighting the need to explore combination therapies. An updated analysis will be presented.
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Ma, Michelle W., Joshua Andrew Farhadian, Erica Brooke Friedman, Eleazar Vega-Saenz de Miera, Douglas Hanniford, Miguel F. Segura, Russell S. Berman, et al. "MicroRNA alterations associated with BRAF status in melanoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8565. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8565.
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8565 Background: We hypothesize that BRAF mutations result in microRNA (miRNA) alterations which contribute to orchestrating the mutant BRAF’s oncogenic effects in melanoma. Our study is the first to examine the association between the BRAF mutation status in primary melanomas and the expression of miRNAs that target known tumor suppressors. Methods: 84 prospectively accrued melanoma patients at New York University Langone Medical Center were studied. DNA and total RNA were extracted from consecutive sections of formalin-fixed paraffin-embedded primary tissues. BRAF mutation status was determined by DNA sequencing. RNA was hybridized to miRCURY miRNA microarrays containing 1314 probes. Normalized miRNA data were analyzed using the t-test (p<0.05) to identify differentially expressed miRNAs between BRAFmut vs. BRAFwt cases. Those with an average fold change (FC) > 2 were selected for predicted (TargetScan, PicTar) and validated (miRWalk) gene target analysis, and overlapping genes targeted by ≥ 2 miRNAs were analyzed using pathway-mapping algorithms (KEGG, BioCarta, PANTHER). Results: 48 (57%) primaries were BRAFwt and 36 (43%) were BRAFmut (26 V600E, 4 V600K, 1 V600R, 1 V600D, 4 other). 30 miRNAs met the criteria for statistically significant differential expression and FC thresholding: let-7i, miR-23c, -26a/b, -27b, -34a, -98, -126*, -141, -148a, -181b, -195, -199a-3p, -199a/b-5p, -200a/b/c, -203, -205, -455-3p, -491-3p, -606, -641, -646, -1297, -4301; miRPlus-C1070, -C1110, -G1246-3p (average FC: 2.3-3.5, all increased in BRAFmut vs. BRAFwt). Predicted and validated target gene analysis revealed 317 genes, of which 110 (35%) were convergent targets of ≥ 2 miRNAs. Pathway analyses of the predicted, validated, and convergent target genes pointed to the potential impact of BRAFmut-associated miRNAs on known tumor suppressors FAS, PTEN, and TNF and the p53 pathway. Conclusions: Differentially expressed miRNAs in BRAFmut vs. BRAFwt primaries target genes with known roles in melanoma biology and/or treatment response. These miRNAs warrant further study as potential effectors of the BRAFmut oncogenic program.
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Karreth, Florian, Markus Reschke, Bjoern Chapuy, Margaret A. Shipp, Roberto Chiarle, and Pier Paolo Pandolfi. "The BRAF Pseudogene Is a Proto-Oncogenic Competitive Endogenous RNA." Blood 124, no. 21 (December 6, 2014): 263. http://dx.doi.org/10.1182/blood.v124.21.263.263.
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Abstract Non-coding RNAs have long been viewed as non-functional genomic relicts of evolution, but recetn findings have implicated their importance in physiology and disease. Recently, in vitro experiments demonstrated that the pseudogenes of PTEN and KRAS operate as natural miRNA decoys (competitive endogenous RNAs or ceRNAs) that regulate the expression of their parental genes. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. To investigate whether the BRAF pseudogene (BRAFps) possesses oncogenic properties we generated transgenic mice carrying a Tet-inducible BRAF pseudogene allele. Global BRAFps overexpression resulted in the development of aggressive B-cell lymphoma after 6-12 months. These tumors were characterized by a profound expansion of B-lymphocytes in the spleen, as well as splenomegaly, lymphadenopathy and infiltration of the kidneys, lungs, and liver by neoplastic cells. The BRAFps-induced lymphoma was polyclonal, transplantable, dependent on continuous BRAFps expression, and cooperated with heterozygous loss of PTEN to accelerate disease onset. Mechanistically, we propose that BRAFps functions as a ceRNA that sequesters miRNAs from BRAF and possibly other targets. Indeed, overexpression of BRAFps results in elevated levels of BRAF in a Dicer-dependent manner. This, in turn, increased BRAF-dependent MAPK signaling and proliferation. To further validate the ceRNA activity of BRAFps, we engineered mice to express only the 3’UTR or CDS of BRAFps as each portion of the pseudogene may individually engage in miRNA-mediated crosstalk with BRAF. Notably, both BRAFps-CDS and BRAFps-3’UTR increased spleen and lymph node weights 6 months after induction. Interestingly, BRAFps-3’UTR elicited a lymphoma phenotype similar to full length BRAFps, while mice expressing BRAFps-CDS developed a more indolent form of this phenotype, suggesting that lymphomagenesis is primarily mediated by the BRAFps 3’UTR. BRAFps transcript was undetectable in primary human B-cells, but was aberrantly expressed in primary human DLBCL and human DLBCL cell lines. Expression of BRAF and BRAFps was positively correlated in human primary DLBCL and human DLBCL cell lines. In addition, gains or amplifications of the genomic locus containing BRAFps were found in various human cancer types. Overexpression of BRAFps in human lymphoma cells elevated BRAF levels, MAPK activation, proliferation and growth in xenografts. Our results demonstrate for the first time the oncogenic potential of a pseudogene in an engineered mouse model and indicate that ceRNA- mediated regulation is an important regulatory mechanism of gene expression in vivo. Disclosures No relevant conflicts of interest to declare.
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Qiang, Ya-Wei, Shiqiao Ye, Yu Chen, Joshua Epstein, Brian A. Walker, Frits van Rhee, Gareth Morgan, and Faith E. Davies. "Mutant KRAS and Brafs Upregulate Stress Granules and Mediate Drug Resistance, Which Can be Modulated By Cox2 Inhibition in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 3166. http://dx.doi.org/10.1182/blood-2018-99-117459.
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Abstract Introduction: Mutant RAS leads to activation of the RAS/RAF/MEK/ERK pathway in approximately 50% of multiple myeloma (MM). Stress granules (SGs) are non-membranous structures composed of translational mRNAs, ribosomal proteins, and RNA-binding proteins, which form in response to different stress stimuli and chemotherapeutic treatment. TheKRAS effector pathway mediates the upregulation of SGs conferring resistance to chemotherapeutic agents in solid tumors. However, it is unclear if SGs are upregulated in KRAS mutant MM and if this is associated with chemotherapeutic resistance. The purpose of this study was to characterize the role of RAS/RAF mutants in SG formation and to provide a molecular rationale for the clinical testing of combinations targeting RAS mutation with inhibition of SG formation. Methods. To investigate the association of RAS mutation status with SG formation, we used two K-RAS mutant positive (KRASM), two BRAF mutant positive (BRAFM),and 2 wildtype KRAS (KRASWT) and wild type BRAF (BRAFWT) MM cell lines as models.We assessed the cellular distribution of SG proteins by immunofluorescence using anti-G3BP and anti-eIF4G antibodies. To establish a quantitative readout for SG formation (SG index), we applied the ImageJ analyze-particle tool to calculate the fraction of the SG area in the total cell area based on G3BP and eIF4G immunofluorescence (SG area/cell area). MTT assays were used to detect the effect of SGs on the survival of MM cells alone or in combination with diclofenac sodium (DS),or bortezomib. Results:Immunofluorescence analysis showed that exposure of KRASM MM cells lines to oxidative stress via treatment with sodium arsenite (SA))was associated with the induction of SGs as indicated by accumulation of cytoplasmic puncta of G3BP and elF4G at high level, compared with RASWTMM cells. Quantitative analysis of SG formation by Image J analyze-particle tool revealed that the SG index for G3BP (13.225 ±3.2) in KRASM was significantly higher compared with KRASWT(2.936 ±1.2,P =0.0004) in response to SA. The SG index for elF4G(32.89 ±6.2) in KRASM was significantly higher than that in KRASWT(4.96, ±2.3, p<5.03E-5). These results indicate that mutant KRAS may play a regulatory role in SG formation. Given that BRAF mutation leads to activation of MAPK pathway, we next determined if BRAF mutants regulate SGs in response to SA. MM cells harboring K601N mutation, showed a high level of induction of SG formation following treatment with SA, compared with BRAFWTcells. The SG index for G3BP (11.52 ±0.89) in BRAFM was significant higher than that in BRAFWTcells (4.02 ±1.92; P=1.03E-6). Similarly, the SG index for elF4G (19.2±1.3) in BRAFMwas significant upregulated compared with BRAFWT(6.3 ±2.8, p=5.3E-5). MM cells harboring BRAF mutation at D4594N displayed intermediate positive of SG formation. These results suggest that the presence of the BRAF mutation promotes SG formation in response to oxidative stress. Since SGs have been shown to contribute to mutant KRAS-mediated resistance to chemotherapeutic reagents in solid tumors and mutant KRAS enhances SG formation by up-regulating cox biosynthesis, we next determine if inhibition of COX2 activity by diclofenac sodium (DS), a pharmacological inhibitor of COX2, was able to overcome Bzb resistance in KRAS and BRAF mutant MM cells. MTT assay showed that the viability index (0.8±0.16) reduced to (0.49 ±0.015) in KRASMMM cells treated by 10 nM of Bortezomib (Bzb) alone or to (0.46 ±0.016) with 200 mM of DS alone. A significant decrease of cell viability (0.22±0.01, P<0.001) was observed when treatment with Bzb and DS were combined. Similar synergistic effects of Bzb and DS were observed in BRAFM cells, compared with BRAFWT. Taken together, these results indicate that inhibition of COX2 activity enhance KRAS and BRAF mutant MM cell sensitivity to proteasome inhibition. Conclusion: Our results suggest that KRAS mutant and BRAF mutant MM cells significantly upregulate SG formation and inhibition of COX2 activity enhances KRAS and BRAF mutant MM cell sensitivity to proteasome inhibition. Further experiments are ongoing to determine the molecular mechanism by which KRAS and BRAF mutant MM cells upregulate SG formation and their role in MM cell resistance to chemotherapeutic reagents. Disclosures Epstein: University of Arkansas for Medical Sciences: Employment. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding. Davies:TRM Oncology: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; Abbvie: Consultancy; TRM Oncology: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; ASH: Honoraria; Janssen: Consultancy, Honoraria.
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Duggan, Megan C., Andrew R. Stiff, Maryam Bainazar, Kelly Regan, Gonzalo N. Olaverria Salavaggione, Sophia Maharry, James S. Blachly, et al. "Identification of NRAS isoform 2 overexpression as a mechanism facilitating BRAF inhibitor resistance in malignant melanoma." Proceedings of the National Academy of Sciences 114, no. 36 (August 21, 2017): 9629–34. http://dx.doi.org/10.1073/pnas.1704371114.
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Activating mutations in BRAF are found in 50% of melanomas and although treatment with BRAF inhibitors (BRAFi) is effective, resistance often develops. We now show that recently discovered NRAS isoform 2 is up-regulated in the setting of BRAF inhibitor resistance in melanoma, in both cell lines and patient tumor tissues. When isoform 2 was overexpressed in BRAF mutant melanoma cell lines, melanoma cell proliferation and in vivo tumor growth were significantly increased in the presence of BRAFi treatment. shRNA-mediated knockdown of isoform 2 in BRAFi resistant cells restored sensitivity to BRAFi compared with controls. Signaling analysis indicated decreased mitogen-activated protein kinase (MAPK) pathway signaling and increased phosphoinositol-3-kinase (PI3K) pathway signaling in isoform 2 overexpressing cells compared with isoform 1 overexpressing cells. Immunoprecipitation of isoform 2 validated a binding affinity of this isoform to both PI3K and BRAF/RAF1. The addition of an AKT inhibitor to BRAFi treatment resulted in a partial restoration of BRAFi sensitivity in cells expressing high levels of isoform 2. NRAS isoform 2 may contribute to resistance to BRAFi by facilitating PI3K pathway activation.
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Xu, Zhiyuan, Cheng-Chia Lee, Arjun Ramesh, Adam C. Mueller, David Schlesinger, Or Cohen-Inbar, Han-Hsun Shih, and Jason P. Sheehan. "BRAF V600E mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases." Journal of Neurosurgery 126, no. 3 (March 2017): 726–34. http://dx.doi.org/10.3171/2016.2.jns1633.
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OBJECTIVE Recent advancements in molecular biology have identified the BRAF mutation as a common mutation in melanoma. The wide use of BRAF kinase inhibitor (BRAFi) in patients with metastatic melanoma has been established. The objective of this study was to examine the impact of BRAF mutation status and use of BRAFi in conjunction with stereotactic radiosurgery (SRS). METHODS This was a single-center retrospective study. Patient's charts and electronic records were reviewed for date of diagnosis of primary malignancy, BRAF mutation status, chemotherapies used, date of the diagnosis of CNS metastases, date of SRS, survival, local tumor control after SRS, and adverse events. Patients were divided into 3 groups: Group A, those with mutant BRAF without BRAFi treatment (13 patients); Group B, those with mutant BRAF with BRAFi treatment (17 patients); and Group C, those with wild-type BRAF (35 patients). Within a cohort of 65 patients with the known BRAF mutation status and treated with SRS between 2010 and 2014, 436 individual brain metastases (BMs) were identified. Kaplan-Meier methodology was then used to compare survival based on each binary parameter. RESULTS Median survival times after the diagnosis of melanoma BM and after SRS were favorable in patients with a BRAF mutation and treated with SRS in conjunction with BRAFi (Group B) compared with the patients with wild-type BRAF (Group C, 23 vs 8 months and 13 vs 5 months, respectively; p < 0.01, log-rank test). SRS provided a local tumor control rate of 89.4% in the entire cohort of patients. Furthermore, the local control rate was improved in the patients treated with SRS in conjunction with BRAFi (Group B) compared with patients with wild-type (Group C) or with BRAF mutation but no BRAFi (Group A) as an adjunct treatment for BMs. CONCLUSIONS BRAF mutation status appears to play an important role as a potent prognostic factor in patients harboring melanoma BM. BRAFi in conjunction with SRS may benefit this group of patients in terms of BM survival and SRS with an acceptable safety profile.
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Cybulska-Stopa, Bozena, Anna Malgorzata Czarnecka, Krzysztof Ostaszewski, Karolina Piejko, Marcin Zietek, Robert Dziura, Ewa Rutkowska, et al. "Is the BRAF mutation still an unfavorable risk factor in patients with metastatic melanoma in the era of modern therapies?" Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21544-e21544. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21544.
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e21544 Background: BRAF-mutated (MUT) melanoma is characterized by specific clinical features including more aggressive biological behavior than BRAF wild-type (WT) melanoma. BRAF mutations are historically known as negative prognostic factor for to shorter overall survival (OS) in patients with stage IV disease with melanoma. Methods: Consecutive patients with unresectable or metastatic melanoma started treatment with BRAF inhibitors (BRAFi), BRAFi and MEK inhibitors (MEKi) or IT (anti-PD-1 antibody) between 1/Jan/2013 and 31/Dec/2020. Clinical factors including age, gender, primary location of melanoma, ECOG performance status, baseline LDH level, and location of metastases, response to treatment were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Dec/2021. Results: In total 1456 patients were enrolled. BRAF mutation was found in 723 (49.7%) patients and 733 (50.3%) patients were BRAF WT. All BRAF WT patients received first-line IT, while BRAF MUT patient received first-line treatment with BRAFi (n = 134/723, 18%), BRAFi and MEKi (n = 426, 58%) or anty-PD-1 (n = 173, 24%). BRAF MUT patients were significantly younger (median 60 vs 69; p < 0.0001), had worse ECOG (p = 0.0008), elevated LDH (p < 0.0001), had higher number of metastatic sites (p < 0.0001) and brain metastases (p < 0.0001). The estimated median OS (mOS) in BRAF WT group was 17.3 month while in BRAF MUT - 14.8 months (p = 0.33; HR = 0.94, Cl 95% 0.8-1.1). mOS in BRAF MUT group treated with BRAFi was - 10.0, while with BRAFi and MEKi combination - 14.9. BRAF WT and BRAF MUT groups treated with IT did not differ significantly in baseline characteristics. BRAF MUT group treated with IT achieved mOS of 26.2 months, while in BRAF WT 17.3 months. Conclusions: The analysis showed no differences in the median OS between BRAF MUT and BRAF WT patients with unresectable or metastatic melanoma treated with novel therapies (BRAFi-MEKi combination or IT), despite unfavorable prognostic factors in the BRAF MUT group. Moreover mOS was significantly prolonged in the BRAF MUT patients treated with IT.
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Cybulska-Stopa, Bozena, Anna Malgorzata Czarnecka, Krzysztof Ostaszewski, Karolina Piejko, Marcin Zietek, Robert Dziura, Ewa Rutkowska, et al. "Is the BRAF mutation still an unfavorable risk factor in patients with metastatic melanoma in the era of modern therapies?" Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21544-e21544. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21544.
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e21544 Background: BRAF-mutated (MUT) melanoma is characterized by specific clinical features including more aggressive biological behavior than BRAF wild-type (WT) melanoma. BRAF mutations are historically known as negative prognostic factor for to shorter overall survival (OS) in patients with stage IV disease with melanoma. Methods: Consecutive patients with unresectable or metastatic melanoma started treatment with BRAF inhibitors (BRAFi), BRAFi and MEK inhibitors (MEKi) or IT (anti-PD-1 antibody) between 1/Jan/2013 and 31/Dec/2020. Clinical factors including age, gender, primary location of melanoma, ECOG performance status, baseline LDH level, and location of metastases, response to treatment were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Dec/2021. Results: In total 1456 patients were enrolled. BRAF mutation was found in 723 (49.7%) patients and 733 (50.3%) patients were BRAF WT. All BRAF WT patients received first-line IT, while BRAF MUT patient received first-line treatment with BRAFi (n = 134/723, 18%), BRAFi and MEKi (n = 426, 58%) or anty-PD-1 (n = 173, 24%). BRAF MUT patients were significantly younger (median 60 vs 69; p < 0.0001), had worse ECOG (p = 0.0008), elevated LDH (p < 0.0001), had higher number of metastatic sites (p < 0.0001) and brain metastases (p < 0.0001). The estimated median OS (mOS) in BRAF WT group was 17.3 month while in BRAF MUT - 14.8 months (p = 0.33; HR = 0.94, Cl 95% 0.8-1.1). mOS in BRAF MUT group treated with BRAFi was - 10.0, while with BRAFi and MEKi combination - 14.9. BRAF WT and BRAF MUT groups treated with IT did not differ significantly in baseline characteristics. BRAF MUT group treated with IT achieved mOS of 26.2 months, while in BRAF WT 17.3 months. Conclusions: The analysis showed no differences in the median OS between BRAF MUT and BRAF WT patients with unresectable or metastatic melanoma treated with novel therapies (BRAFi-MEKi combination or IT), despite unfavorable prognostic factors in the BRAF MUT group. Moreover mOS was significantly prolonged in the BRAF MUT patients treated with IT.
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Park, Jongwhi, Hope Lancero, Emon Nasajpour, Cesar Garcia, Laura Prolo, Gerald Grant, and Claudia Petritsch. "STEM-15. THERAPY-INDUCED CHANGES BY BRAF AND MEK INHIBITORS IN BRAF V600E-MUTATED GLIOMA MODELS PROVIDE POTENTIAL NOVEL THERAPEUTIC OPPORTUNITIES." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii34. http://dx.doi.org/10.1093/neuonc/noac209.132.
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Abstract Combinations of the MEK inhibitor trametinib, and BRAF inhibitor dabrafenib (BRAFi+MEKi) show rapid and sustained responses in patients with BRAF V600E-mutated low-grade glioma, but tumor rebound after treatment discontinuation is frequent. Moreover, a lack of response is common in patient with high-grade glioma raising the need for further research into BRAFi+MEKi effects on tumors. We showed previously that BRAF V600E-mutated glioma cells positive for CD133 (Prominin-1), a marker of brain tumor stem cells, show decreased sensitivity to BRAFi, indicative of their role in promoting therapy resistance. BRAF V600E-mutated murine and patient-derived glioma cell lines (STN-10049, SU-aGBM5) were generated and together with established BRAF V600E-mutated cell lines (DBTRG, AM38) were analyzed for changes in gene expression in response to 48 hrs treatment with BRAFi dabrafenib and MEKi trametinib. Cells were analyzed by RNA-seq and gene enrichment analyses while cell culture supernatant was analyzed for cytokine production using an ELISA. Syngeneic, orthotopic BRAF V600E-mutated tumor allograft-bearing mice were treated with BRAFi+MEKi, with therapeutic antibodies against immune checkpoint molecules (anti-PD-L1 and anti-CTLA-4) and with combination of all four agents, and tumors were analyzed by mass cytometry and immunofluorescence for stem and T cell markers. BRAFi+MEKi treatment induced an interferon gamma (IFNg) response gene signature in BRAF V600E-mutated glioma cells and increased HLA gene expression. The frequency of tumor-infiltrating CD4+ CD8+ T cells in syngeneic BRAF V600E-mutated tumor allografts increased with BRAFi+MEKi treatment. Combining BRAFi+MEKi with anti-PD-L1 and anti-CTLA-4 treatment decreased CD133+ cells more effectively than either therapy alone, and resulted in a T cell-dependent survival benefit of mice with orthotopic BRAF V600E-mutated high-grade glioma. Combination of BRAFi+MEKi with immune checkpoint inhibition should be further explored as a viable option to prevent tumor rebound and therapy resistance in patients with BRAF V600E-mutated glioma.
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Wichmann, Jürgen, Caroline Rynn, Thomas Friess, Jeannine Petrig-Schaffland, Martin Kornacker, Cornelia Handl, Jasmin Emmenegger, et al. "Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor." Clinical Cancer Research 28, no. 4 (November 15, 2021): 770–80. http://dx.doi.org/10.1158/1078-0432.ccr-21-2761.
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Abstract Purpose: Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi. Experimental Design: The novel, brain penetrant, paradox breaker BRAFi is comprehensively characterized in vitro, ex vivo, and in several preclinical in vivo models of melanoma mimicking peripheral disease, brain metastatic disease, and acquired resistance to first-generation BRAFi. Results: Compound Ia manifested elevated potency and selectivity, which triggered cytotoxic activity restricted to BRAF-mutated models and did not induce RAF paradoxical activation. In comparison to approved BRAFi at clinical relevant doses, this novel agent showed a substantially improved activity in a number of diverse BRAF V600E models. In addition, as a single agent, it outperformed a currently approved BRAFi/MEKi combination in a model of acquired resistance to clinically available BRAFi. Compound Ia presents high central nervous system (CNS) penetration and triggered evident superiority over approved BRAFi in a macro-metastatic and in a disseminated micro-metastatic brain model. Potent inhibition of MAPK by Compound Ia was also demonstrated in patient-derived tumor samples. Conclusions: The novel BRAFi demonstrates preclinically the potential to outperform available targeted therapies for the treatment of BRAF-mutant tumors, thus supporting its clinical investigation.
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Gebhardt, Kathleen, Bayram Edemir, Elisabeth Groß, Linda Nemetschke, Stefanie Kewitz-Hempel, Rose K. C. Moritz, Cord Sunderkötter, and Dennis Gerloff. "BRAF/EZH2 Signaling Represses miR-129-5p Inhibition of SOX4 Thereby Modulating BRAFi Resistance in Melanoma." Cancers 13, no. 10 (May 15, 2021): 2393. http://dx.doi.org/10.3390/cancers13102393.
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Many melanomas are associated with activating BRAF mutation. Targeted therapies by inhibitors of BRAF and MEK (BRAFi, MEKi) show marked antitumor response, but become limited by drug resistance. The mechanisms for this are not fully revealed, but include miRNA. Wishing to improve efficacy of BRAFi and knowing that certain miRNAs are linked to resistance to BRAFi, we wanted to focus on miRNAs exclusively associated with response to BRAFi. We found increased expression of miR-129-5p during BRAFi treatment of BRAF- mutant melanoma cells. Parallel to emergence of resistance we observed mir-129-5p expression to become suppressed by BRAF/EZH2 signaling. In functional analyses we revealed that miR-129-5p acts as a tumor suppressor as its overexpression decreased cell proliferation, improved treatment response and reduced viability of BRAFi resistant melanoma cells. By protein expression analyses and luciferase reporter assays we confirmed SOX4 as a direct target of mir-129-5p. Thus, modulation of the miR-129-5p-SOX4 axis could serve as a promising novel strategy to improve response to BRAFi in melanoma.
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Tanaka, Yuka, Maho Murata, Che-Hung Shen, Masutaka Furue, and Takamichi Ito. "NECTIN4: A Novel Therapeutic Target for Melanoma." International Journal of Molecular Sciences 22, no. 2 (January 19, 2021): 976. http://dx.doi.org/10.3390/ijms22020976.
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Malignant melanoma is the most common lethal skin cancer and causes death in a short time when metastasized. Although BRAF inhibitors (BRAFi) have greatly improved the prognosis of BRAF-mutated melanoma, drug resistance is a major concern even when they are combined with MEK inhibitors. Alternative treatments for BRAFi-resistant melanoma are highly anticipated. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed and associated with progression in tumors. We aimed to investigate the role of NECTIN4 in melanoma and its potency as a therapeutic target using 126 melanoma samples and BRAFi-resistant cells. Immunohistochemically, most of the clinical samples expressed NECTIN4, at least in part. NECTIN4 was highly expressed in BRAF-mutated melanoma and its high expression was associated with disease-free survival. In BRAFi-resistant melanoma cells, NECTIN4 and the PI3K/Akt pathway were upregulated, along with the acquisition of BRAFi resistance. Monomethyl auristatin E, a cytotoxic part of NECTIN4-targeted antibody–drug conjugate, was effective for BRAF-mutated or BRAFi-resistant melanoma cells. NECTIN4 inhibition increased the sensitivity of BRAFi-resistant cells to BRAFi and induced apoptosis. In conclusion, we revealed the expression and roles of NECTIN4 in melanoma. Targeted therapies against NECTIN4 can be a novel treatment strategy for melanoma, even after the acquisition of BRAFi resistance.
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Menzer, Christian, Alexander M. Menzies, Matteo S. Carlino, Irene Reijers, Emma J. Groen, Thomas Eigentler, Jan Willem B. de Groot, et al. "Targeted Therapy in Advanced Melanoma With Rare BRAF Mutations." Journal of Clinical Oncology 37, no. 33 (November 20, 2019): 3142–51. http://dx.doi.org/10.1200/jco.19.00489.
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PURPOSE BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K–mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively ( P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.
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Goldinger, Simone M., Carla Murer, Pascale Stieger, and Reinhard Dummer. "Upstream MAPK pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9071. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9071.
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9071 Background: The presence of activating BRAF mutations in about 60% of all metastatic melanomas (mM) has led to the development of inhibitors (i) targeting the RAF and MEK kinases. MEK is the downstream effector of BRAF. However, the blockage of the MAPK pathway is limited due to the development of resistance mechanisms. MEK resistance can confer cross-resistance to BRAF inhibition, whereas BRAF resistance is independent from the MAPK pathway. Hence, it seems reasonable to start a MAPK pathway inhibition by a BRAFi. An upstream inhibition beginning the treatment reversed with a MEKi followed by a BRAFi has not yet been clinically explored. Methods: Patients at the Dermatology Department of the University Hospital of Zurich with mM harboring a BRAF mutation formed the study cohort. Patients were divided into a group who was treated initially with a BRAFi (vemurafenib or LGX818) followed by a MEKi (AZD6244, trametinib, or MEK 162), and a group who first received a MEKi and was later treated with a BRAFi. Duration of disease control (DDC) was measured in time from the initiation of the treatment to discontinuation due to disease progression or toxicity. Results: A total of 16 patients (7 females, 9 males, age 30-73 years) with BRAF mutated mM were evaluated. The median DDC (mDDC) was similar in both groups. When patients were treated first with a BRAFi (n=7), the mDDC for BRAFi was 7.6 and for MEKi 1.7 months, respectively. In contrast, when the treatment sequence was inversed (n=9), the mDDC for MEKi was 3.9 and for BRAFi 4.7 months. We observed some benefit (partial response, stable disease) using chemotherapy after BRAFi/MEKi progression. Conclusions: This analysis indicates that the sequential MEK-RAF inhibition of the MAPK pathway is acceptable in BRAF mutant mM patients. The sum of the DDC of both groups (9.3 and 8.6 months) is comparable to the promising BRAFi/MEKi combination therapy (median PFS 9.4 months). Besides the sequenced administration analyzed here, an intermittent administration should be further studied.
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Pelster, Meredith S., and Rodabe N. Amaria. "Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials." Therapeutic Advances in Medical Oncology 11 (January 2019): 175883591983082. http://dx.doi.org/10.1177/1758835919830826.
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The development of BRAF and MEK inhibitors (BRAFis and MEKis) and immune checkpoint inhibitors have changed the management of advanced stage melanoma and improved the outcomes of patients with this malignancy. However, both therapeutic approaches have limitations, including a limited duration of benefit in subsets of BRAF-mutant melanoma patients treated with targeted therapy and a lower overall response rate without a clear predictive biomarker in patients treated with checkpoint inhibitors. Preclinical and translational data have shown that BRAFis and MEKis alter the tumor microenvironment to make it more amenable to immunotherapy and have provided the scientific rationale for combing BRAFis and MEKis with immunotherapy. In this review, the initial studies demonstrating the impact of BRAFis and MEKis on the expression of melanoma differentiation antigens, T-cell infiltration, and the balance of immune stimulatory and immune suppressive cells and cytokines are addressed. Preclinical work on the combination of targeted therapy with BRAFis and MEKis with immunotherapy are reviewed, highlighting improved tumor responses in mouse models of BRAF-mutated melanoma treated with combinatorial strategies. Lastly, data from early clinical trials of combined targeted therapy and immunotherapy are discussed, focusing on response rates and toxicities.
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Nobre, Liana, Michal Zapotocky, Vijay Ramaswamy, Scott Ryall, Julie Bennett, Julia Balaguer Guill, Lorena Baroni, et al. "PDCT-08. SUPERIOR OUTCOME FOR BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION." Neuro-Oncology 21, Supplement_6 (November 2019): vi184—vi185. http://dx.doi.org/10.1093/neuonc/noz175.771.
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Abstract BACKGROUND Children with pediatric low grade glioma’s (PLGG) harboring BRAF V600E mutation have poor outcome due to relative resistance to chemo-radiation and higher risk of malignant transformation. However, the role of targeted BRAF inhibition in these tumors is poorly defined. METHODS We assembled an international cohort of children with BRAF V600E mutant gliomas treated with BRAF inhibition, from 29 centers participating in the PLGG taskforce, and collected response, survival and molecular parameters. RESULTS Sixty-seven patients were treated with BRAFi (56 PLGG and 11 high grade gliomas) for a median time of 17.4 months (6 – 61 months), with 13 PLGG treated upfront. Objective responses was observed in 80% of PLGG patients compared to 28% with conventional chemotherapy (p< 0.001). Rapid responses were observed in most PLGG patients (median of 4 months), sustained in 86% of tumors up to 5 years while on therapy. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. Seventeen patients with PLGG discontinued BRAFi and 76.5% (13/17) progressed rapidly after discontinuation (median time 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies such as concomitant homozygous deletion of CDKN2A or H3K27M mutation were not associated with lack of response to BRAFi. Overall these responses translated to 2-year progression-free survival of 0.636 (95%CI 0.505–0.802) and 0.43 (95% CI 0.32–0.57) for BRAFi and chemotherapy treated BRAF V600E PLGG respectively (p=0.003). CONCLUSION The use of BRAFi results in objective, robust and durable responses in BRAF V600E PLGG and is associated with favorable survival. Larger prospective studies will be required to determine appropriate regiments, and long-term functional outcomes with BRAFi therapy in childhood gliomas.
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Hicks, Hannah M., Veronica L. Espinoza, Sharon B. Sams, Nikita Pozdeyev, and Rebecca E. Schweppe. "Abstract 2434: The role of a more invasive phenotype in response to MAPK-directed therapies in thyroid cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2434. http://dx.doi.org/10.1158/1538-7445.am2022-2434.
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Abstract Advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) are the leading causes of endocrine cancer death. Mutations in the MAP kinase (MAPK) pathway are common in PTC and ATC, especially in BRAF, with a prevalence of 40-60%. Despite the importance of the MAPK pathway in thyroid cancer, therapies targeting this pathway are not approved for BRAF-mutant PTC patients. While the combination of BRAF and MEK inhibition is approved for patients with BRAF-mutant ATC, these patients often progress. An emerging mechanism of resistance to targeted therapies is an invasive phenotype switch in which cells transition from a proliferative, therapy sensitive population to an invasive, therapy resistant population. Here, we sought to determine whether increased invasion plays a role in resistance to BRAFi in BRAF-mutant PTC and ATC. In our panel of BRAF-mutant PTC and ATC cell lines with varying sensitivity/resistance to the BRAF inhibitor dabrafenib (BRAFi), we showed that cells resistant to BRAFi exhibit a 1.8 to 2.2 fold increase (p<0.04) in invasion while sensitive cells do not. Using Reverse Phase Protein Array, we identified a 2.0-fold increase in the extracellular matrix protein, fibronectin (FN1), in response to BRAFi treatment. We further identified a 1.6 to 3.2 fold increase (p<0.02) in FN1 secretion in resistant cell lines and found that conditioned media from BRAFi-treated resistant cells promotes invasion 3.8 to 5.7-fold (p<0.0048). Accordingly, treatment with FN1 phenocopies BRAFi-treatment by increasing invasion 1.9 to 2.1 fold (p<0.04), and depletion of FN1 blocks this increase in invasion. Resistant cells with depleted FN1 also fail to exhibit a BRAFi-induced increase in secreted FN1. MAPK pathway reactivation is a common mechanism of resistance to inhibitors of the MAPK pathway, which we have shown can be blocked by dual BRAF and ERK inhibition (Hicks, HM; McKenna, LR et al. Mol Carcinog. 60(3) 2021). ERK inhibition also mitigates the increase in invasion observed in response to single-agent BRAFi (p<0.0014) or FN1 (p<0.0271) in resistant cells. We further observed that dual inhibition of BRAF and ERK slows tumor growth in vivo in a BRAFi-resistant patient-derived xenograft model (p=0.02). These data indicate that thyroid cancer cells resistant to BRAF inhibition exhibit a more invasive phenotype characterized by an increase in FN1 and a pro-invasive secretome. Dual inhibition of BRAF and ERK ablates this BRAFi-driven increase in invasion and slows tumor growth in vivo, providing a potential therapeutic strategy for BRAF-mutant thyroid cancer patients. Citation Format: Hannah M. Hicks, Veronica L. Espinoza, Sharon B. Sams, Nikita Pozdeyev, Rebecca E. Schweppe. The role of a more invasive phenotype in response to MAPK-directed therapies in thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2434.
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Kefford, Richard, Wilson H. Miller, Daniel Shao-Weng Tan, Ryan J. Sullivan, Georgina Long, Rodrigo Dienstmann, Wai Meng David Tai, et al. "Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9029. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9029.
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9029 Background: Clinical data indicate that combining a BRAF and a MEK inhibitor (BRAFi, MEKi) may be more effective than BRAFi monotherapy in BRAF-mutant metastatic melanoma and that a MEKi may overcome or delay resistance to a BRAFi. Methods: This ongoing phase 1b/2 study is evaluating the combination of LGX818, a potent, selective BRAF inhibitor, and MEK162, a selective MEK1/2 inhibitor, in BRAFi-naive and -pretreated patients with BRAF-mutant tumors. The objective of the phase 1b part is to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) for oral, daily LGX818 + MEK162 in BRAF V600–mutant advanced solid tumors. A Bayesian logistic regression model with overdose control guides the treatment dose escalation. Results: As of January 8, 2013, 20 patients (7 BRAFi-naive melanoma; 9 BRAFi-pretreated melanoma; 2 BRAFi-naive thyroid cancer; 1 BRAFi-naive metastatic colorectal cancer; 1 BRAFi-pretreated colorectal cancer) were treated with LGX818 qd + MEK162 bid at the following dose levels (DLs): 50 mg + 45 mg, 100 mg + 45 mg, 200 mg + 45 mg, and 400 mg + 45 mg. No dose-limiting toxicity has been observed at these DLs. The next DL of 600 mg + 45 mg is under investigation. The single agent RP2Ds for LGX818 and MEK162 are 450 mg and 45 mg, respectively. The most common adverse events (≥ 20%, all grades) suspected to be treatment related were nausea, abdominal pain, and headache. No events of fever, hand-foot-skin reactions, hyperkeratosis, or squamous cell carcinoma were observed. In patients with at least 1 post-baseline CT scan available for investigator-determined response, a complete response was observed in 1/7 (14%) BRAFi-naïve melanoma patients and partial responses were observed in 5/7 (71%) BRAFi-naive melanoma patients, 2/9 (22%) BRAFi-pretreated melanoma patients (starting at 50 mg + 45 mg DL), and 1/2 thyroid cancer patients. Conclusions: Preliminary data from this study indicate that LGX818 + MEK162 can be safely combined with promising clinical benefit. No febrile events or photosensitivity were reported suggesting a distinct safety profile for this BRAFi/MEKi combination vs others. Clinical trial information: NCT01543698.
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Rossi, Ernesto, Giovanni Schinzari, Francesco Cellini, Mario Balducci, Mariangela Pasqualoni, Brigida Anna Maiorano, Bruno Fionda, et al. "Dabrafenib-Trametinib and Radiotherapy for Oligoprogressive BRAF Mutant Advanced Melanoma." Biomedicines 11, no. 2 (January 29, 2023): 394. http://dx.doi.org/10.3390/biomedicines11020394.
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The clinical management of metastatic melanoma has been changed by BRAF (BRAFi) and MEK inhibitors (MEKi), which represent a standard treatment for BRAF-mutant melanoma. In oligoprogressive melanoma patients with BRAF mutations, target therapy can be combined with loco-regional radiotherapy (RT). However, the association of BRAF/MEK inhibitors and RT needs to be carefully monitored for potential increased toxicity. Despite the availability of some reports regarding the tolerability of RT + target therapy, data on simultaneous RT and BRAFi/MEKi are limited and mostly focused on the BRAFi vemurafenib. Here, we report a series of metastatic melanoma patients who received fractioned RT regimens for oligoprogressive disease in combination with the BRAFi dabrafenib and the MEKi trametinib, which have continued beyond progression. None of the cases developed relevant adverse events while receiving RT or interrupted dabrafenib and trametinib administration. These cases suggest that a long period of dabrafenib/trametinib interruption during radiotherapy for oligoprogressive disease can be avoided. Prospective trials are warranted to assess the efficacy and safety of the contemporary administration of BRAF/MEK inhibitors and radiotherapy for oligoprogressive disease.
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Nobre, Liana, Michal Zapotocky, Vijay Ramaswamy, Scott Ryall, Julie Bennet, Daniel Alderete, Julia Balaguer Guill, et al. "LGG-55. OUTCOME OF BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii377. http://dx.doi.org/10.1093/neuonc/noaa222.433.
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Abstract Children with pediatric gliomas harboring BRAF V600E mutation have a poor outcome with current chemoradiation strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. We collected clinical, imaging, molecular and outcome information from BRAF V600E glioma patients treated with BRAFi across 29 centers from multiple countries. Sixty-seven patients were treated with BRAFi (56 pediatric low grade gliomas, PLGG and 11 pediatric high grade gliomas, PHGG) for up to 5.6 years. Objective responses were observed in 80% of PLGGs compared to 28% with conventional chemotherapy (p<0.001). These responses were rapid (median, 4 months), and sustained in 86% of tumors up to 5 years while on therapy. PLGG which discontinued BRAFi, 76.5% (13/17) progressed rapidly after discontinuation (median 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with a lack of response to BRAFi. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95%CI, 35.3% to 69.5%) vs 29.8% (95% CI, 20% to 44.4%) for BRAFi vs chemotherapy respectively (p=0.02). The use of BRAFi results in robust and durable responses while on therapy in BRAF V600E PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAFi therapy in childhood gliomas.
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Muldoon, Daniel, Guisheng Zhao, Carly Batt, Mallika Singh, and Theodore Nicolaides. "MODL-17. SHP2 INHIBITORS SHOW ACTIVITY AGAINST NF1-DEFICIENT GLIOMAS AND ENHANCE MAPK PATHWAY INHIBITION IN BRAF-V600E MUTANT GLIOMAS." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii414. http://dx.doi.org/10.1093/neuonc/noaa222.591.
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Abstract INTRODUCTION Activation of the RAS-MAPK signaling cascade is common in pediatric gliomas. Based on the role of SHP2 in RAS pathway signaling, we hypothesized that NF1-deficient pediatric glioma models would respond to SHP2 inhibitor monotherapy whereas BRAF-V600E gliomas would not. However, we postulated that the latter would exhibit increased sensitivity to a BRAF inhibitor (BRAFi) in combination with SHP2i. Here we demonstrate that the SHP2 inhibitors SHP099 and RMC-4550 (SHP2i) show significant single-agent activity in vitro against NF1-deficient glioma cells and that the combination of RMC-4550 with BRAFi shows increased activity in BRAF-V600E glioma cells relative to the single-agents. METHODS Using a panel of NF1 mutant/deficient and BRAF-V600E mutant glioma cell lines we examined effects on cell viability and protein expression levels of total and phosphorylated MEK, ERK, and AKT. RESULTS LN229 and U87 NF1-deficient glioma cells are sensitive to SHP2i alone but not A375 cells (melanoma, BRAF-V600E). Additionally, we show that in multiple BRAF-V600E glioma cell lines BRAFi sensitivity increases when combined with a SHP2i. Immunoblots show decreased expression of pERK and pMEK in LN229 cells following SHP2i exposure, while A375 cells maintain MAPK pathway signaling. A sustained decrease in the expression of pERK after 24 hours was observed in BRAF-V600E glioma cells with BRAFi in combination with SHP2i, consistent with relief of feedback inhibition. In vivo studies using orthotopic xenograft models are underway. CONCLUSION SHP2i shows preclinical activity in vitro against NF1-deficient pediatric glioma cell lines as a single-agent and against BRAF-V600E gliomas in combination with BRAFi.
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Madej, Ewelina, Anna A. Brożyna, Agnieszka Adamczyk, Norbert Wronski, Agnieszka Harazin-Lechowska, Anna Muzyk, Krzysztof Makuch, Michal Markiewicz, Janusz Rys, and Agnieszka Wolnicka-Glubisz. "Vemurafenib and Dabrafenib Downregulates RIPK4 Level." Cancers 15, no. 3 (February 1, 2023): 918. http://dx.doi.org/10.3390/cancers15030918.
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Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular targets are sought that could completely inhibit melanoma progression. Since receptor-interacting protein kinase (RIPK4) probably functions as an oncogene in melanoma and its structure is similar to the BRAF protein, we analyzed the impact of vemurafenib and dabrafenib on RIPK4 in melanomas. The in silico study confirmed the high similarity of BRAF kinase domains to the RIPK4 protein at both the sequence and structural levels and suggests that BRAFi could directly bind to RIPK4 even more strongly than to ATP. Furthermore, BRAFi inhibited ERK1/2 activity and lowered RIPK4 protein levels in BRAF-mutated melanoma cells (A375 and WM266.4), while in wild-type BRAF cells (BLM and LoVo), both inhibitors decreased the level of RIPK4 and enhanced ERK1/2 activity. The phosphorylation of phosphatidylethanolamine binding protein 1 (PEBP1)—a suppressor of the BRAF/MEK/ERK pathway—via RIPK4 observed in pancreatic cancer did not occur in melanoma. Neither downregulation nor upregulation of RIPK4 in BRAF- mutated cells affected PEBP1 levels or the BRAF/MEK/ERK pathway. The downregulation of RIPK4 inhibited cell proliferation and the FAK/AKT pathway, and increased BRAFi efficiency in WM266.4 cells. However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors.
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Uebel, Anne, Stefanie Kewitz-Hempel, Edith Willscher, Kathleen Gebhardt, Cord Sunderkötter, and Dennis Gerloff. "Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma." International Journal of Molecular Sciences 24, no. 3 (January 19, 2023): 1963. http://dx.doi.org/10.3390/ijms24031963.
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Activating BRAF mutations occurs in 50–60% of malignant melanomas. Although initially treatable, the development of resistance to BRAF-targeted therapies (BRAFi) is a major challenge and limits their efficacy. We have previously shown that the BRAFV600E signaling pathway mediates the expression of EZH2, an epigenetic regulator related to melanoma progression and worse overall survival. Therefore, we wondered whether inhibition of EZH2 would be a way to overcome resistance to vemurafenib. We found that the addition of an EZH2 inhibitor to vemurafenib improved the response of melanoma cells resistant to BRAFi with regard to decreased viability, cell-cycle arrest and increased apoptosis. By next-generation sequencing, we revealed that the combined inhibition of BRAF and EZH2 dramatically suppresses pathways of mitosis and cell cycle. This effect was linked to the downregulation of Polo-kinase 1 (PLK1), a key regulator of cell cycle and proliferation. Subsequently, when we inhibited PLK1, we found decreased cell viability of melanoma cells resistant to BRAFi. When we inhibited both BRAF and PLK1, we achieved an improved response of BRAFi-resistant melanoma cells, which was comparable to the combined inhibition of BRAF and EZH2. These results thus reveal that targeting EZH2 or its downstream targets, such as PLK1, in combination with BRAF inhibitors are potential novel therapeutic options in melanomas with BRAF mutations.
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Schreck, Karisa, Andrew Morin, Guisheng Zhao, Bridget Sanford, Adam Green, Kenneth Jones, Anurhada Banerjee, et al. "DDRE-13. DECONVOLUTING MECHANISMS OF RESISTANCE TO BRAF INHIBITORS IN BRAF V600E HUMAN GLIOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii64. http://dx.doi.org/10.1093/neuonc/noaa215.258.
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Abstract BACKGROUND While BRAF-targeted therapy can be effective in a subset of patients with glioma, resistance to treatment can emerge over time. The description and validation of mechanisms of resistance in BRAF-mutant glioma are not previously described. METHODS Pre- and post- BRAF inhibitor (BRAFi) or BRAFi/MEK inhibitor (MEKi) treated patient samples were obtained under IRB-approved protocols at University of Colorado Denver, UCSF, and Johns Hopkins. Targeted DNA sequencing or whole exome sequencing (WES), and RNA-seq were conducted on paired samples. Functional validation of putative resistance mechanisms was performed using established glioma cell lines with BRAF V600E mutation (DBTRG-5MG, AM38, B76). RESULTS Analysis of 15 tissue sample pairs identified point mutations in 15 genes (including CBL, NF1, PTEN, and MAP2K1) and expression changes in RAF1 leading to putative mechanisms of resistance. We performed functional validation of loss of NF1 and CBL as resistance mechanisms and demonstrated growth inhibition and cell death in response to BRAFi with siRNA/sgRNA-mediated knockdown of each gene. Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN-/-) restored sensitivity to BRAFi. Ingenuity pathway analysis suggested that a switch from BRAF to CRAF dependence mediated resistance in some tumors. Indeed, inhibition of CRAF expression using siRNA in a patient-derived glioma cell line re-sensitized cells to BRAFi. CONCLUSIONS Analysis of pre-/post-treatment BRAF mutant glioma sample pairs, primarily from pediatric patients, identified a variety of putative resistance mechanisms, some of which have been validated in vitro. Resistance mechanisms to BRAFi in glioma are varied and may be susceptible to different combinations of targeted therapy, highlighting the importance of a personalized approach.
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Romano, David, Lucía García-Gutiérrez, Nourhan Aboud, David J. Duffy, Keith T. Flaherty, Dennie T. Frederick, Walter Kolch, and David Matallanas. "Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma." Life Science Alliance 5, no. 10 (August 29, 2022): e202201445. http://dx.doi.org/10.26508/lsa.202201445.
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The RAS-RAF-MEK-ERK pathway is hyperactivated in most malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors (BRAFi) are highly efficient for treating patients with BRAFV600E mutations, but tumours frequently acquire resistance within a few months. Multiple resistance mechanisms have been identified, due to mutations or network adaptations that revive ERK signalling. We have previously shown that RAF proteins inhibit the MST2 proapoptotic pathway in a kinase-independent fashion. Here, we have investigated the role of the MST2 pathway in mediating resistance to BRAFi. We show that the BRAFV600E mutant protein, but not the wild-type BRAF protein, binds to MST2 inhibiting its proapoptotic signalling. Down-regulation of MST2 reduces BRAFi-induced apoptosis. In BRAFi-resistant cell lines, MST2 pathway proteins are down-regulated by ubiquitination and subsequent proteasomal degradation rendering cells refractory to MST2 pathway–induced apoptosis. Restoration of apoptosis can be achieved by increasing MST2 pathway protein expression using proteasome inhibitors. In summary, we show that the MST2 pathway plays a role in the acquisition of BRAFi resistance in melanoma.
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Thompson, Elizabeth L., Jiayi J. Hu, and Laura J. Niedernhofer. "The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma." Cancers 13, no. 9 (May 7, 2021): 2241. http://dx.doi.org/10.3390/cancers13092241.
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BRAF is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic BRAF missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF inhibitors (BRAFi) have been developed to specifically inhibit BRAFV600 mutations that improve melanoma survival, but resistance and secondary cancer often occur. Causal mechanisms of BRAFi-induced secondary cancer and resistance have been identified through upregulation of MAPK and alternate pro-survival pathways. In addition, overriding of cellular senescence is observed throughout the progression of disease from benign nevi to malignant melanoma. In this review, we discuss melanoma BRAF mutations, the genetic mechanism of BRAFi resistance, and the evidence supporting the role of senescent cells in melanoma disease progression, drug resistance and secondary cancer. We further highlight the potential benefit of targeting senescent cells with senotherapeutics as adjuvant therapy in combating melanoma.
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Wattson, Daniel A., Helen Alice Shih, Andrzej Niemierko, Ryan M. Merritt, Donald P. Lawrence, Kevin S. Oh, Ryan J. Sullivan, and Keith Flaherty. "Survival patterns following brain metastases for patients with melanoma in the targeted therapy era." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9064. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9064.
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9064 Background: Survival from metastatic melanoma (MM) has been significantly prolonged with the introduction of molecularly targeted therapy, including BRAF inhibitors (BRAFi) for patients (pts) with the V600E mutation. Here, we present the first data describing patterns of survival after diagnosis of brain metastases (BM) in a large cohort of these pts with long follow-up. Methods: A retrospective review of 191 MM pts accrued on multiple prospective trials between 2008–2012 was conducted. These trials assessed novel immunologic and targeted therapies in pts with both BRAF mutant (n=70) and wild type/unknown (n=121) tumors. We evaluated pt characteristics and the impact of systemic and BM-directed treatments. Results: Of 98 pts who developed BM, median follow-up after first BM was 7.7 months (15.5 months for the 25 living pts), and 33 were treated with BRAFi. Median duration of BRAFi use was 5.9 months (range 0.7–27.1), which preceded BM in 30%, was concurrent with first BM in 18%, and followed first BM in 52%. Ipilimumab or anti–PD-1/PD-L1 immunotherapy was given to 58% of pts who received a BRAFi and 95% of those who did not. Limited intracranial disease on initial BM presentation (defined as ≤3 lesions) occurred in 70% of BRAFi-treated pts and 74% of non-BRAFi pts, and 70% of BRAFi pts received at least one focal BM treatment (stereotactic radiosurgery or resection) compared to 75% of non-BRAFi pts. As shown in the Table, actuarial survival after BM diagnosis was prolonged among pts treated with a BRAFi. This is due primarily to the nearly 2-year median survival of pts for whom a BRAFi was initiated after BM were diagnosed. Conclusions: Survival for pts with BM from BRAF mutant MM can significantly exceed the often anticipated 4–6 months, particularly if a BRAFi is initiated after BM arise. This supports BRAFi activity in intracranial disease, and helps to inform trials currently under way testing BRAFi use among MM pts with previously diagnosed BM. [Table: see text]
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Čepulytė, Rūta, Andrius Žučenka, and Valdas Pečeliūnas. "Combination of Dabrafenib and Trametinib for the Treatment of Relapsed and Refractory Multiple Myeloma Harboring BRAF V600E Mutation." Case Reports in Hematology 2020 (October 15, 2020): 1–5. http://dx.doi.org/10.1155/2020/8894031.
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Multiple myeloma (MM) is an incurable plasma cell neoplasia characterized by relapsed and/or refractory (R/R) disease course, which poses a major therapeutic challenge. New therapies, including BRAF V600E mutation targeting, may become a new treatment option for R/R MM. In combination with mitogen-activated protein kinase inhibitors (MEKi), BRAF inhibitors (BRAFi) could provide better tailored clinical management, although experience in this field is lacking. To this date, there is only one case describing R/R MM treatment with BRAFi vemurafenib and MEKi cobimetinib. This is the first case presenting a R/R MM patient treated with BRAFi dabrafenib and MEKi trametinib.
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Park, Robin, Laércio Lopes da Silva, Sunggon Lee, and Anwaar Saeed. "Impact of BRAF mutations on prognosis and immunotherapy response in microsatellite instability/mismatch repair deficient metastatic colorectal cancer: A systematic review and meta-analysis." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3557. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3557.
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3557 Background: Mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC) defines a molecular subtype with distinct clinicopathologic characteristics including an excellent response to immunotherapy. Although BRAF mutations are established as a negative prognostic marker in CRC, whether they retain their negative prognostic impact in or alter the response to immunotherapy in dMMR/MSI-H CRC remains unknown. Herein, we present a systematic review and meta-analysis of the impact of BRAF mutations on the overall survival (OS) and immune checkpoint inhibitor (ICI) response in dMMR/MSI-H CRC. Methods: Studies published from inception to 26 January 2021 were searched in PubMed, Embase, and major conference proceedings (AACR, ASCO, and ESMO). Eligible studies included the following: 1) observational studies reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients and 2) experimental studies of ICI reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients. A summary hazard ratio (HR) was calculated for OS in BRAF mutated ( BRAFmut) vs. BRAF wild type ( BRAFwt) patients (pts) with the random effects meta-analysis (REM). A summary odds ratio (OR) was calculated for objective response rate (ORR) in BRAFmut vs. BRAFwt pts treated with ICI with the REM. Results: Database search conducted according to PRISMA guidelines found 4221 studies in total. Initial screening identified 30 studies and after full-text review, 9 studies (N = 4158 pts) were included for the meta-analysis of prognosis (analysis A) and 3 studies (N = 178 pts) were included for the meta-analysis of ICI response (analysis B). The outcome measures are summarized in the table below. Analysis A showed that in stage I-IV dMMR/MSI-H CRC pts, BRAFmut was associated with worse OS than BRAFwt (HR 1.57, 1.23-1.99). The heterogeneity was low (I2 = 21%). Subgroup analysis showed no significant difference in the prognostic impact of BRAF mutation status between stage IV only and stage I-IV CRC pts. Analysis B showed no difference in ORR (OR 1.04, 0.48-2.25) between BRAFmut vs. BRAFwt dMMR/MSI-H pts who received ICI. The heterogeneity was low (I2 = 0%). Conclusions: BRAF mutations retain their negative prognostic impact in dMMR/MSI-H stage I-IV and stage IV CRC but are not associated with differential ICI response. Limitations include the following: analysis A was based on retrospective studies; also, the impact of BRAF status on the survival outcome of ICI could not be assessed due to limited number of studies.[Table: see text]
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Röck, Ruth, Johanna E. Mayrhofer, Omar Torres-Quesada, Florian Enzler, Andrea Raffeiner, Philipp Raffeiner, Andreas Feichtner, et al. "BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS." Science Advances 5, no. 8 (August 2019): eaav8463. http://dx.doi.org/10.1126/sciadv.aav8463.
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Oncogenic BRAF mutations initiate tumor formation by unleashing the autoinhibited kinase conformation and promoting RAS-decoupled proliferative RAF-MEK-ERK signaling. We have engineered luciferase-based biosensors to systematically track full-length BRAF conformations and interactions affected by tumorigenic kinase mutations and GTP loading of RAS. Binding of structurally diverse αC-helix-OUT BRAF inhibitors (BRAFi) showed differences in specificity and efficacy by shifting patient mutation–containing BRAF reporters from the definitive opened to more closed conformations. Unexpectedly, BRAFi engagement with the catalytic pocket of V600E-mutated BRAF stabilized an intermediate and inactive kinase conformation that enhanced binary RAS:RAF interactions, also independently of RAF dimerization in melanoma cells. We present evidence that the interference with RAS interactions and nanoclustering antagonizes the sequential formation of drug-induced RAS:RAF tetramers. This suggests a previously unappreciated allosteric effect of anticancer drug-driven intramolecular communication between the kinase and RAS-binding domains of mutated BRAF, which may further promote paradoxical kinase activation and drug resistance mechanisms.
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Kotecha, Rupesh, Jacob A. Miller, Vyshak A. Venur, Alireza M. Mohammadi, Samuel T. Chao, John H. Suh, Gene H. Barnett, et al. "Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome." Journal of Neurosurgery 129, no. 1 (July 2018): 50–59. http://dx.doi.org/10.3171/2017.1.jns162797.
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OBJECTIVEThe goal of this study was to investigate the impact of stereotactic radiosurgery (SRS), BRAF status, and targeted and immune-based therapies on the recurrence patterns and factors associated with overall survival (OS) among patients with melanoma brain metastasis (MBM).METHODSA total of 366 patients were treated for 1336 MBMs; a lesion-based analysis was performed on 793 SRS lesions. The BRAF status was available for 78 patients: 35 had BRAFmut and 43 had BRAF wild-type (BRAF-WT) lesions. The Kaplan-Meier method evaluated unadjusted OS; cumulative incidence analysis determined the incidences of local failure (LF), distant failure, and radiation necrosis (RN), with death as a competing risk.RESULTSThe 12-month OS was 24% (95% CI 20%–29%). On multivariate analysis, younger age, lack of extracranial metastases, better Karnofsky Performance Status score, and fewer MBMs, as well as treatment with BRAF inhibitors (BRAFi), anti–PD-1/CTLA-4 therapy, or cytokine therapy were significantly associated with OS. For patients who underwent SRS, the 12-month LF rate was lower among those with BRAFmut lesions (6%, 95% CI 2%–11%) compared with those with BRAF-WT lesions (22%, 95% CI 13%–32%; p < 0.01). The 12-month LF rates among lesions treated with BRAFi and PD-1/CTLA-4 agents were 1% (95% CI 1%–4%) and 7% (95% CI 1%–13%), respectively. On multivariate analysis, BRAF inhibition within 30 days of SRS was protective against LF (HR 0.08, 95% CI 0.01–0.55; p = 0.01). The 12-month rates of RN were low among lesions treated with BRAFi (0%, 95% CI 0%–0%), PD-1/CTLA-4 inhibitors (2%, 95% CI 1%–5%), and cytokine therapies (6%, 95% CI 1%–13%).CONCLUSIONSPrognostic schema should incorporate BRAFi or immunotherapy status and use of targeted therapies. Treatment with a BRAF inhibitor within 4 weeks of SRS improves local control without an increased risk of RN.
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Leclair, Héloïse M., Nina Tardif, Anaïs Paris, Marie-Dominique Galibert, and Sébastien Corre. "Role of Flavonoids in the Prevention of AhR-Dependent Resistance During Treatment with BRAF Inhibitors." International Journal of Molecular Sciences 21, no. 14 (July 16, 2020): 5025. http://dx.doi.org/10.3390/ijms21145025.
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BRAF and MEK inhibitors (BRAFi and MEKi) are the standard of care for the treatment of metastatic melanoma in patients with BRAFV600E mutations, greatly improving progression-free survival. However, the acquisition of resistance to BRAFi and MEKi remains a difficult clinical challenge, with limited therapeutic options available for these patients. Here, we investigated the therapeutic potential of natural flavonoids as specific AhR (Aryl hydrocarbon Receptor) transcription factor antagonists in combination with BRAFi. Experimental Design: Experiments were performed in vitro and in vivo with various human melanoma cell lines (mutated for BRAFV600E) sensitive or resistant to BRAFi. We evaluated the role of various flavonoids on cell sensitivity to BRAFi and their ability to counteract resistance and the invasive phenotype of melanoma. Results: Flavonoids were highly effective in potentiating BRAFi therapy in human melanoma cell lines by increasing sensitivity and delaying the pool of resistant cells that arise during treatment. As AhR antagonists, flavonoids counteracted a gene expression program associated with the acquisition of resistance and phenotype switching that leads to an invasive and EMT-like phenotype. Conclusions: The use of natural flavonoids opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.
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Dummer, Reinhard, Caroline Robert, Marta Nyakas, Grant A. McArthur, Ragini Reiney Kudchadkar, Carlos Gomez-Roca, Ryan J. Sullivan, et al. "Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9028. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9028.
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9028 Background: LGX818, a potent and selective BRAF inhibitor (BRAFi) being investigated in BRAF V600 mutant melanoma, has unique biochemical properties with a dissociation half-time > 10 times longer than other BRAF inhibitors. Methods: A phase I trial of LGX818 administered orally once (qd) or twice (bid) daily in BRAF V600 tumors was initiated to define the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and to assess pharmacokinetics and clinical activity in BRAFi–naive or pretreated patients with BRAF V600 mutant advanced melanoma. Baseline assessment of biomarkers from MAPK/PI3K pathways and pharmacodynamics were also evaluated. Results: Fifty-four patients have been enrolled in the dose-escalation phase (dose levels [DLs], 50-700 mg qd [n=42] and 75-150 mg bid [n=12]). LGX818 plasma concentrations increased proportionally by dose with a mean t1/2 of 4 hours and steady state in ≈ 15 days. The MTD/RP2D (450 mg qd) was well tolerated. Seven patients had a dose limiting toxicity (DLT): 5 at qd (1 each with hand-foot skin reaction [HFSR], foot pain, fatigue, diarrhea/rash, insomnia/asthenia) and 2 at bid (1 facial paresis/confusion, 1 musculoskeletal pain/neuralgia). All DLTs were grade 3 and reversible. The most common adverse events (≥ 20%) suspected to be treatment related were cutaneous (rash, dry skin, HFSR, pruritus, keratosis pilaris, alopecia), pain in extremity, arthralgia, and fatigue. Squamous cell carcinoma was observed in 2 patients (1 naive and 1 pretreated). As of 30 Sept 2012, the preliminary efficacy (all DLs) in patients with at least 1 postbaseline tumor assessment was 16 partial responses [PRs] (67%; 12 confirmed) out of 24 BRAFi–naive patients and 2 PRs (8.3%; 1 confirmed) among 24 BRAFi–pretreated patients. Responses were seen at all DLs from 50 to 550 mg qd. Updated safety and efficacy including time to event endpoints will be reported. Conclusions: Initial results from this study identified the MTD/RP2D as 450 mg/day and provided an early sign of promising activity in advanced melanoma. Expansion cohorts are ongoing in BRAFi–naive and BRAFi–pretreated melanoma and colorectal cancer. Clinical trial information: NCT01436656.
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Haselmann, Verena, Christoffer Gebhardt, Ingrid Brechtel, Angelika Duda, Claudia Czerwinski, Antje Sucker, Tim Holland-Letz, Jochen Utikal, Dirk Schadendorf, and Michael Neumaier. "Liquid Profiling of Circulating Tumor DNA in Plasma of Melanoma Patients for Companion Diagnostics and Monitoring of BRAF Inhibitor Therapy." Clinical Chemistry 64, no. 5 (May 1, 2018): 830–42. http://dx.doi.org/10.1373/clinchem.2017.281543.
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Abstract BACKGROUND The current standard for determining eligibility of patients with metastatic melanoma for BRAF-targeted therapy is tissue-based testing of BRAF mutations. As patients are rarely rebiopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumor mutational status in real time and thereby representing a noninvasive biomarker for monitoring BRAF therapy. METHODS In all, 634 stage I to IV melanoma patients were enrolled at 2 centers, and 1406 plasma samples were prospectively collected. Patients were assigned to 3 separate study cohorts: study 1 for assessment of circulating tumor DNA (ctDNA) as part of companion diagnostics, study 2 for assessment of ctDNA for patients with low tumor burden and for follow-up, and study 3 for monitoring of resistance to BRAF inhibitor (BRAFi) or mitogen-activated protein kinase inhibitor therapy. RESULTS Overall, a high degree of concordance between plasma and tissue testing results was observed at 90.9% (study 1) and 90.1% (study 2), respectively. Interestingly, discrepant results were in some cases associated with nonresponse to BRAFi (n = 3) or a secondary BRAF-mutant malignancy (n = 5). Importantly, ctDNA results correlated with the clinical course of disease in 95.7% and with response to treatment. Significantly, the detection of BRAF mutant ctDNA preceded relapse assessed by Response Evaluation Criteria in Solid Tumors, and was more specific than serum S100 and lactate dehydrogenase. CONCLUSIONS Blood-based testing compares favorably with standard-of-care tissue-based BRAF mutation testing. Importantly, blood-based BRAF testing correlates with the clinical course, even for early-stage patients, and may be used to predict response to treatment, recurrence, and resistance before radioimaging under BRAFi therapy, thereby enabling considerable improvements in patient treatment.
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Huynh, Sandra, Laurent Mortier, Caroline Dutriaux, Eve Maubec, Marie Boileau, Olivier Dereure, Marie-Therese Leccia, et al. "Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study." Cancers 12, no. 6 (June 23, 2020): 1666. http://dx.doi.org/10.3390/cancers12061666.
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Despite significant progress in melanoma survival, therapeutic options are still needed in case of progression under immune checkpoint inhibitors (ICI), and resistance to targeted therapies (TT) in BRAF-mutated melanomas. This study aimed to assess the safety of combined ICI and TT as a rescue line in real-life clinical practice. We conducted a study within the prospective French multicentric MelBase cohort, including patients treated with a combination of anti-PD1 (pembrolizumab/nivolumab) and BRAF inhibitor (BRAFi: dabrafenib/vemurafenib) and/or MEK inhibitors (MEKi: trametinib/cobimetinib) for BRAF mutated or wild-type advanced melanoma. Fifty-nine patients were included: 30% received the triple combination, 34% an anti-PD1 and BRAFi, and 36% an anti-PD1 and MEKi. Grade 3–4 adverse events occurred in 12% of patients. Permanent discontinuation or dose reduction of one of the treatments for toxicity was reported in 14% and 7% of patients, respectively. In the BRAF wild-type subgroup, treatment with MEKi and anti-PD1 induced a tumor control rate of 83% and median progression-free survival of 7.1 months. The combination of anti-PD1 and BRAFi and/or MEKi was a safe rescue line for advanced melanoma patients previously treated with ICI/TT. The benefit of these combinations, specifically anti-PD1 and MEKi in BRAF wild-type melanoma patients, needs to be prospectively studied.
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Switzer, Benjamin, Sabah Alaklabi, Arya Mariam Roy, Kristopher Attwood, Chong Wang, Lamya Hamad, Tammy Sessanna, Michele Nanni, Yeliam Patel, and Igor Puzanov. "Toxicity and outcomes of BRAF and MEK inhibitor “ramp-up” dosing strategies for patients with melanoma: A real-world institutional experience." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21600-e21600. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21600.
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e21600 Background: Combination BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy is a widely accepted treatment option for patients (pts) with BRAF-V600E mutant melanoma. Although effective, these combinations exhibit high rates of adverse events (AEs), with 44% - 66% requiring dose modification or interruption and up to 26% discontinuing due to AEs in the adjuvant setting. Enhanced tolerance to BRAFi/MEKi is expected to improve pts quality of life and potentially enhance clinical outcomes. Clinicians at Roswell Park Comprehensive Cancer Center (RPCCC) have implemented a dose escalation regimen upon initiation of BRAFi/MEKi in efforts to enhance the tolerance of these combinations for pts with BRAF-V600E mutant melanoma in the adjuvant and advanced setting. Here we present a retrospective analysis of the toxicity profiles and outcomes associated with this “ramp-up” approach. Methods: Pts presenting to RPCCC in Buffalo, NY for management of stage III or IV melanoma harboring BRAF-V600E mutations were retrospectively observed from 1/2012 to 12/2020. Pts starting BRAFi/MEKi combinations, regardless of prior lines of therapy, were included unless concurrently receiving immune checkpoint inhibition. The “ramp-up” regimen involves a 25% dose of BRAFi and 50% dose of MEKi, which is gradually increased over 4 weekly intervals until full dose is achieved. Pts started on full-dose BRAFi/MEKi were included as a comparison arm. Observations included 1) demographics, 2) treatment regimens and disruptions, 3) rate and severity of AEs, 4) outcomes including best overall response rates (ORR), progression-free survival (PFS) and overall survival (OS). Results: A total of 88 pts were analyzed (21 and 35 receiving “ramp-up” BRAFi/MEKi in the adjuvant and advanced (unresectable stage III or stage IV) setting, respectively, and 32 received full-dose (non-ramp-up) BRAFi/MEKi in the advanced setting). Demographics were similar except pts in the “ramp-up” cohorts were higher in average age (62.0 vs 56.0, p = 0.032) than pts starting at full-dose. Pts receiving adjuvant BRAFi/MEKi at “ramp-up” dosing exhibited a 4.8% (n = 1) rate of grade 3 or higher (Gr3+) AEs and 33.3% (n = 7) AE-related discontinuation rate (9.9 month average time to discontinuation). In the advanced setting, “ramp-up” vs full-dose treated pts exhibited Gr3+ AE rates of 25.7% (n = 9) vs 43.8% (n = 14; p = 0.197) and AE-related discontinuation rates of 34.4% (n = 12) vs 40.6% (n = 13; p = 0.592), respectively. Trends in overall AEs, ORR, PFS, and OS were similar to historical observations across all groups. Conclusions: This real-world analysis suggests that “ramp-up” incremental dosing of BRAFi/MEKi for pts with melanoma in the adjuvant and advanced setting may improve the tolerance and toxicity profiles of these agents without compromising their clinical efficacy, and may be of particular utility in pts with advanced age.
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San Lucas, F. Anthony, Scott Kopetz, Paul A. Scheet, and Eduardo Vilar Sanchez. "Discovering new targeted therapies for BRAF mutant-like colorectal cancers." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3623. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3623.
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3623 Background: Approximately 10% of colorectal cancers (CRCs) harbor a BRAF mutation (BRAFm). Patients with BRAFm tumors have poor prognosis and are a therapeutic challenge. A BRAFm gene expression signature has been communicated (Popovici et al, JCO 2012), which can identify BRAFm tumors as well as BRAF wild-type tumors that display a similar expression pattern. Collectively, these tumors are termed BRAFm-like. Our goal was to validate this signature using next-generation sequencing and to discover novel therapies for BRAFm-like CRCs using a systems biology approach. Methods: We developed a semi-automated workflow that integrates publicly available tools named the Cancer In-silico Drug Discovery (CIDD). To validate the BRAFm-like signature, we used CIDD to analyze the CRC dataset from the The Cancer Genome Atlas Network (TCGA). Samples were stratified on BRAFm status using exome-sequencing, and expression profiles were inferred from RNA-sequencing. We matched expression profiles with drug-induced signatures inferred from the Connectivity Map (CMap) – a systems biology tool that contains expression data of cell lines treated with 1,500 compounds. CIDD statistically ranks candidate compounds and annotates them to pathways using public databases. Results: When applied to TCGA RNA-sequencing data, a classifier based on the BRAFm-like signature resulted in 93.3% sensitivity and 83.5% specificity for detecting BRAFm samples. When applied to Agilent gene expression data, this resulted in 80% sensitivity and 91.1% specificity. 41% of KRAS-mutated samples and 14% of double wild-type samples were predicted to be BRAFm-like. 100% of MSI-high and 18% of MSS samples were predicted to be BRAFm-like. Compounds near the top of our drug rankings include Gefitinib and MG-262 a proteasome inhibitor. Conclusions: We have validated the BRAFm-like signature using RNA-sequencing and Agilent expression data from the TCGA, and showed a high degree of robustness across technologies. We have identified EGFR and proteasome inhibitors as potential compounds to target BRAFm-like CRCs.
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Póvoa, Antónia Afonso, Elisabete Teixeira, Maria Rosa Bella-Cueto, Rui Batista, Ana Pestana, Miguel Melo, Thalita Alves, et al. "Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma." Cancers 13, no. 9 (April 23, 2021): 2048. http://dx.doi.org/10.3390/cancers13092048.
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Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM.
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Weber, Jeffrey S., Keith T. Flaherty, Jeffrey R. Infante, Gerald Steven Falchook, Richard Kefford, Adil Daud, Omid Hamid, et al. "Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8510. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8510.
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8510 Background: In preclinical models, the BRAFi/MEKi combination has demonstrated enhanced activity against BRAF-mutant cancer cells compared with either drug alone, delayed emergence of BRAFi resistance, and prevented BRAFi-related proliferative skin lesions. A 3-part study investigating the dabrafenib/trametinib combination was conducted in patients (pts) with V600 BRAF mutant solid tumors. Interim data from the study were previously reported (Infante, ASCO 2011); updated safety and efficacy data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and measurable disease according to RECIST 1.1. Pts were treated on 4 escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are reported. Results: Among 77 melanoma pts, median age was 52 years, 61% male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response rate for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24). Median PFS (months) for each dose level, respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 adverse events (AEs), pneumonia and hyponatraemia. The most common G3/4 AEs were pyrexia (n=6, 5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ G2 occurred in 17 (14%) pts. Cutaneous squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 (2%). Conclusions: The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.