Somatic mutations in BRAF have been found in 1--4% of all NSCLC most of which are adenocarcinomas. The G466V mutation results in an amino acid substitution within the kinase domain of BRAF. Unlike other mutant BRAF proteins, G466V shows decreased kinase activity. In preclinical studies, lung cancer cell lines with G466V mutation were sensitive to TKI dasatinib, presumably by induction of tumor cell senescence. However, therapeutic implications of BRAF inhibitors in patients with this mutation need to be fully elucidated. Drug: Trametinib

BRAF is part of the mitogen-activated protein kinase (MAPK) signaling pathway. BRAF G466V is a missense mutation which impairs BRAF kinase activity but paradoxically activates MEK and ERK through transactivation of c-RAF. This variant is associated with decreased cell proliferation and cell viability as compared to wild-type BRAF. This variant is a rare BRAF mutation and accounts for < 1% of BRAF mutations in colorectal adenocarcinoma. A single preclinical study of BRAF G466V in colon cancer demonstrated sensitivity to anti-EGFR tyrosine kinase therapy (cetuximab) and a MEK inhibitor (trametinib), however, there was no benefit seen with the RAF inhibitor vermurafinib. The clinicopathologic significance of BRAF G466V remains to be fully elucidated.