BRAFmutant

BRAF-mutant refers to cancers in which mutations in the BRAF gene lead to constitutive activation of the MAPK/ERK signaling pathway, promoting cell proliferation and survival. The most common alteration is the V600E substitution, but a spectrum of other mutations exists that can affect signaling and response to therapy.

BRAF mutations are categorized into three functional classes. Class I includes V600 mutations that signal as active monomers independent of RAS. Class II comprises non-V600 mutations that signal as constitutively active dimers. Class III includes kinase-impaired variants that depend on upstream RAS signaling and often require other pathway alterations for signaling. This classification has implications for treatment and resistance patterns.

Frequency and distribution vary by tumor type. BRAF mutations are most frequent in melanoma, where V600E accounts for the majority of BRAF-mutant cases, and they also occur in papillary thyroid carcinoma and colorectal cancer, among others. The overall frequency is highest in melanoma and generally lower in colorectal and lung cancers. Specific mutation patterns and coexisting alterations influence clinical behavior and therapy choices.

Detection relies on molecular testing, including targeted sequencing panels and PCR-based assays. Immunohistochemistry can screen for the V600E protein but confirmatory sequencing is common to characterize the exact mutation and classify the tumor.

Targeted therapy for BRAF-mutant tumors includes BRAF inhibitors (such as vemurafenib and dabrafenib), often combined with MEK inhibitors (such as trametinib or cobimetinib). This combination improves response rates and survival in melanoma and is used in other cancers with BRAF V600 mutations, including some NSCLC and colorectal cancer, though colorectal cancer often requires additional strategies due to distinct biology. Resistance frequently develops through reactivation of MAPK signaling or activation of parallel pathways, guiding ongoing research into combination regimens and sequencing with immunotherapy.