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Characterization of BRAF Thr599dup Mutation as a Targetable Driver Mutation Identified in Lung Adenocarcinoma by Comprehensive Genomic Profiling.
- Source :
-
JCO precision oncology [JCO Precis Oncol] 2024 Apr; Vol. 8, pp. e2300538. - Publication Year :
- 2024
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Abstract
- Purpose: Understanding the function of BRAF mutants is crucial for determining the best treatment strategy. This study aimed to characterize a rare BRAF variant, BRAF <superscript>Thr599dup</superscript> , which was identified in a patient with lung adenocarcinoma (LUAD) by comprehensive genomic profiling.<br />Materials and Methods: We report a case of LUAD with BRAF <superscript>Thr599dup</superscript> treated with dabrafenib and trametinib. We conditionally expressed wild-type BRAF, BRAF <superscript>V600E</superscript> , or BRAF <superscript>Thr599dup</superscript> in Ba/F3 cells and BEAS-2B cells. Ba/F3 cells carrying double-mutant BRAF (BRAF <superscript>Thr599dup/R509H</superscript> , BRAF <superscript>V600E/R509H</superscript> , or BRAF <superscript>K601E/R509H</superscript> ) that lacked the dimerizing ability were also established. Knockout of endogenous BRAF or CRAF in Ba/F3-BRAF <superscript>Thr599dup</superscript> cells and Ba/F3-BRAF <superscript>V600E</superscript> 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.<br />Results: The patient was revealed to have BRAF <superscript>Thr599dup</superscript> -positive tumor cells as a predominant clone, and dabrafenib and trametinib treatment showed modest efficacy. In Ba/F3 cells, both BRAF <superscript>Thr599dup</superscript> and BRAF <superscript>V600E</superscript> similarly caused interleukin-3-independent proliferation and activated the MAPK pathway. Moreover, BRAF <superscript>Thr599dup</superscript> and BRAF <superscript>V600E</superscript> similarly caused a significant increase in the anchorage-independent growth ability of BEAS-2B cells. Along with Ba/F3-BRAF <superscript>V600E</superscript> cells, Ba/F3-BRAF <superscript>Thr599dup</superscript> 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-BRAF <superscript>Thr599dup</superscript> cells was not affected, which was in contrast to the findings in the BRAF <superscript>K601E/R509H</superscript> double-mutant model.<br />Conclusion: BRAF <superscript>Thr599dup</superscript> is a potent driver oncogene that activates the MAPK pathway without the requirement for dimerization in vitro. Because BRAF <superscript>Thr599dup</superscript> has been recurrently reported across various cancer types, our findings should be further investigated both mechanistically and clinically.
- Subjects :
- Humans
Pyrimidinones therapeutic use
Imidazoles therapeutic use
Pyridones therapeutic use
Oximes therapeutic use
Female
Male
Proto-Oncogene Proteins B-raf genetics
Adenocarcinoma of Lung genetics
Adenocarcinoma of Lung drug therapy
Lung Neoplasms genetics
Lung Neoplasms drug therapy
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 2473-4284
- Volume :
- 8
- Database :
- MEDLINE
- Journal :
- JCO precision oncology
- Publication Type :
- Academic Journal
- Accession number :
- 38662982
- Full Text :
- https://doi.org/10.1200/PO.23.00538