BRAF and melanoma: Since that a series of mechanisms facilitate MAPK pathway hyper-activation and make melanoma cells refractory to sole BRAF inhibitor, combined inhibition of MEK is subsequently evaluated, and encouraging outcomes have been obtained in two phase III clinical trials COMBI-v and COMBI-d.436,437 Compared to previous single BRAF-targeted therapy, combined inhibition of both BRAF and MEK lead to the upregulation of clinical response rate from 50% to 60–70%.