BRAF/MEK Pathway — Melanoma

The MAPK signalling cascade (RAS-RAF-MEK-ERK) transmits extracellular growth signals from receptor tyrosine kinases to the nucleus, governing cell proliferation, differentiation, and survival. BRAF is a serine/threonine kinase in this cascade, normally activated transiently by RAS-GTP. The BRAF V600E substitution (valine to glutamic acid at codon 600) introduces a negative charge mimicking the phosphorylated activation loop, rendering BRAF constitutively active in a RAS-independent manner. This leads to sustained MEK1/2 and ERK1/2 phosphorylation, driving uncontrolled proliferation. BRAF V600E occurs in approximately 50% of melanomas, 10-15% of colorectal cancers, 50% of papillary thyroid cancers, and smaller proportions of NSCLC, glioma, and hairy cell leukaemia.

BRAF V600E inhibitor monotherapy (vemurafenib, dabrafenib) produces dramatic initial responses in melanoma but is limited by rapid acquired resistance emerging within months, mediated predominantly by paradoxical MAPK pathway reactivation — including RAS mutation, RAF dimerisation, and MAPK amplification. Dual BRAF plus MEK inhibitor combination therapy (dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib) delays resistance by blocking the reactivated MEK-ERK signalling that bypasses BRAF inhibition, significantly improving PFS and OS in metastatic melanoma versus monotherapy. In the adjuvant setting, dabrafenib/trametinib for 12 months demonstrates relapse-free survival benefit in resected stage III BRAF V600E/K melanoma.

The sequencing of targeted therapy and immunotherapy in BRAF-mutant melanoma remains an area of clinical consideration, with both modalities offering substantial but distinct mechanisms of durable response. BRAF/MEK inhibitor combinations in BRAF-mutant NSCLC (dabrafenib/trametinib) and BRAF-mutant thyroid cancer (dabrafenib/trametinib in differentiated thyroid cancer, cabozantinib in radioiodine-refractory disease) reflect the tumour-agnostic but histology-context-dependent nature of BRAF targeting. BRAF fusions (rather than V600 point mutations), predominantly occurring in paediatric low-grade glioma, activate BRAF kinase via a distinct dimerisation-dependent mechanism and are targeted by MEK inhibitors and the pan-RAF inhibitor tovorafenib.