Targeting oncogenic BRAF and aberrant MAPK activation in the treatment of cutaneous melanoma

• The Mitogen activated protein kinase (MAPK) pathway is overactive in melanoma, most commonly because of mutations in BRAF.
• BRAF and MEK inhibitors improve survival in BRAFV600 mutant melanoma.
• The combination of a BRAF and MEK inhibitor improves response rate and survival and also reduces toxicities due to BRAF inhibitor induced paradoxical MAPK pathway activation.
• Resistance to MAPK inhibitors occurs via multiple mechanisms most of which lead to reactivation of the MAPK pathway.
• Combinations of MAPK inhibitors with immunotherapeutic agents are a priority area for clinical and translational research.

BRAF and MEK inhibitors, alone or in combination, are highly active in the 40% of patients with BRAF mutant metastatic melanoma. Despite this activity resistance often develops in patients treated with these agents. This review summarises the biology of the mitogen activated protein kinase (MAPK) pathway, with particular reference to the effects of BRAF and MEK inhibitors in BRAF mutant melanoma. The clinical and molecular predictors of response and mechanisms of resistance are discussed in detail along with the biological rationale and evidence for future treatment strategies in both MAPK inhibitor naïve and resistant BRAF mutant melanoma.