B-Raf(G466V) (BRAF G466V)

B-Raf(G466V) is a missense mutation in the protein kinase domain of the B-Raf serine/threonine kinase (UniProt), encoded by the BRAF gene on chromosome 7, resulting in a glycine-to-valine substitution at position 466. This class III BRAF alteration impairs direct BRAF kinase activity but paradoxically activates the MAPK pathway through heterodimerization with wild-type CRAF, leading to transactivation of MEK and ERK signaling. Found in cancers such as non-small cell lung carcinoma (NSCLC), colorectal cancer, and lung adenocarcinoma, it drives cell proliferation and tumor growth despite low intrinsic kinase activity. Preclinical studies show sensitivity to MEK inhibitors like trametinib, which reduce ERK signaling and inhibit proliferation, and combinations like dabrafenib + trametinib that enhance apoptosis. However, it confers resistance to classical BRAF V600 inhibitors like vemurafenib, with no benefit observed in clinical cohorts. EGFR inhibitors (cetuximab, erlotinib, osimertinib) and novel RAF degraders (CFT1946) demonstrate preclinical efficacy in relevant models. As a rare non-V600 mutation, BRAF G466V represents an actionable target in precision oncology, particularly for MAPK pathway blockade in RAS/NF1 wild-type contexts. Ongoing trials explore its inclusion for solid tumors.

Other names

BRAF p.G466VBRAF c.1397G>T

Inhibits MEK/ERK signaling (trametinib), induces apoptosis (dasatinib), inhibits proliferation via RAF degradation (CFT1946), inhibits ERK phosphorylation (RMC-4550, PF-07799933), transactivation of CRAF leading to paradoxical MEK/ERK activation despite impaired BRAF kinase activity