Biological challenges of BRAF inhibitor therapy.

Activating mutations in BRAF, a constituent of the map kinase pathway, were first discovered as being most prevalent in melanoma in 2002. Only recently have potent and selective, orally available inhibitors of BRAF emerged for clinical testing and demonstrated clear evidence of tumor regression in the majority of patients whose tumors harbor a BRAF mutation. While these early observations suggest that the BRAF targeted therapy will become part of the standard treatment paradigm for patients with advanced melanoma, it is also clear that a majority of these responses are incomplete and temporary. Therefore, the focus of the melanoma field has shifted to understanding the limits of the first generation of selective BRAF inhibitors with regard to safety and efficacy, the context of somatic genetic changes that accompany BRAF, and the combination regimens that target distinct elements of melanoma pathophysiology.