BRAFMEK

BRAFMEK refers to combination therapies that inhibit both BRAF and MEK kinases in the MAPK/ERK signaling pathway. The most common target is the BRAF V600 mutation, which causes constitutive activation of MEK and ERK and uncontrolled cell growth. BRAF inhibitors block mutant BRAF, while MEK inhibitors block downstream MEK1/2 kinases.

Rationale and mechanism of synergy: BRAF inhibitors alone can cause paradoxical activation of MAPK signaling in cells with wild-type BRAF, underscoring the benefit of adding a MEK inhibitor which reduces this paradoxical activation and delays resistance.

Clinical use: The combination of BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) with MEK inhibitors (trametinib, cobimetinib, binimetinib) is approved for unresectable or metastatic melanoma with BRAF V600 mutations, and is under study in other BRAF-mutant tumors.

Outcomes and adverse effects: In melanoma, combinations improve response rates and progression-free survival versus BRAF inhibitor monotherapy and generally have a more favorable skin toxicity profile, though they add MEK-related effects such as edema, liver enzyme elevations, ocular toxicity, and cardiomyopathy risks.

Resistance and research: Tumors can acquire resistance through NRAS mutations, BRAF amplification, MEK mutations, or RTK upregulation; ongoing research explores triplet therapies, sequencing strategies, and biomarkers to predict response.