Reference Detail

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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