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Ref Type Journal Article
PMID (38662982)
Authors Watanabe H, Inoue Y, Karayama M, Yazawa S, Mochizuka Y, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Enomoto N, Fujisawa T, Shinmura K, Inui N, Suda T
Title Characterization of BRAFThr599dup Mutation as a Targetable Driver Mutation Identified in Lung Adenocarcinoma by Comprehensive Genomic Profiling.
Journal Vol Issue Date Pages Journal Short Title
JCO precision oncology 8 2024 Apr e2300538 JCO Precis Oncol
URL
Abstract Text Understanding the function of BRAF mutants is crucial for determining the best treatment strategy. This study aimed to characterize a rare BRAF variant, BRAFThr599dup, which was identified in a patient with lung adenocarcinoma (LUAD) by comprehensive genomic profiling.We report a case of LUAD with BRAFThr599dup treated with dabrafenib and trametinib. We conditionally expressed wild-type BRAF, BRAFV600E, or BRAFThr599dup in Ba/F3 cells and BEAS-2B cells. Ba/F3 cells carrying double-mutant BRAF (BRAFThr599dup/R509H, BRAFV600E/R509H, or BRAFK601E/R509H) that lacked the dimerizing ability were also established. Knockout of endogenous BRAF or CRAF in Ba/F3-BRAFThr599dup cells and Ba/F3-BRAFV600E cells was performed using the CRISPR/Cas9 system. Cell viability, mitogen-activated protein kinase (MAPK) signaling activity, and sensitivity to dabrafenib and trametinib were evaluated.The patient was revealed to have BRAFThr599dup-positive tumor cells as a predominant clone, and dabrafenib and trametinib treatment showed modest efficacy. In Ba/F3 cells, both BRAFThr599dup and BRAFV600E similarly caused interleukin-3-independent proliferation and activated the MAPK pathway. Moreover, BRAFThr599dup and BRAFV600E similarly caused a significant increase in the anchorage-independent growth ability of BEAS-2B cells. Along with Ba/F3-BRAFV600E cells, Ba/F3-BRAFThr599dup cells were highly sensitive to a monomer-specific BRAF inhibitor, dabrafenib, with a half-maximal inhibitory concentration value of 29.7 nM. In the absence of wild-type BRAF, wild-type CRAF, or an intact dimer interface, the ability to induce oncogenic addiction and MAPK pathway activation in Ba/F3-BRAFThr599dup cells was not affected, which was in contrast to the findings in the BRAFK601E/R509H double-mutant model.BRAFThr599dup is a potent driver oncogene that activates the MAPK pathway without the requirement for dimerization in vitro. Because BRAFThr599dup has been recurrently reported across various cancer types, our findings should be further investigated both mechanistically and clinically.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BRAF T599dup duplication gain of function BRAF T599dup (also referred to T599_V600insT) indicates the insertion of the duplicate amino acid, threonine (T)-599, in the protein kinase domain of the Braf protein (UniProt.org). T599dup results in increased kinase activity (PMID: 21190184), increased phosphorylation of Mek and Erk, and transformation in cell culture (PMID: 21190184, PMID: 38662982).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF T599dup Advanced Solid Tumor sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited downstream signaling and viability in transformed cells expressing BRAF T599dup in culture (PMID: 38662982). 38662982
BRAF T599dup Advanced Solid Tumor sensitive Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, Tafinlar (dabrafenib) inhibited downstream signaling and viability in transformed cells expressing BRAF T599dup in culture (PMID: 38662982). 38662982
BRAF T599dup lung adenocarcinoma predicted - sensitive Dabrafenib + Trametinib Case Reports/Case Series Actionable In a clinical case study, treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) resulted in 12.3% tumor shrinkage in a patient with lung adenocarcinoma harboring BRAF T599dup along with KRAS Q61H, however, treatment was discontinued for adverse events (PMID: 38662982). 38662982