ABSTRACT
The central role of BRAF mutations in the progression of most melanomas makes it an excellent target for therapy. BRAF mutations were first identified in melanoma following a genome-wide screen performed at the Sanger Institute in Cambridge, United Kingdom. It is little exaggeration to say that the discovery of activating BRAF mutations in over 60% of melanomas has revolutionized the expectations for targeted therapy in melanoma. Maximizing the therapeutic value of mitogen-activated protein kinase pathway inhibition is the central focus of clinical trials with novel RAS, RAF, and MEK inhibitors. The in vitro data supporting a role for BRAF as the major melanoma oncogene are compelling. Activating mutations in BRAF also drive other processes important for melanoma progression. Clinical trials of sorafenib monotherapy yielded little response, and in in vivo human melanoma mouse xenograft studies, sorafenib was associated with cytostasis and limited tumor regression.
