Resistance to RAF inhibitors revisited.

In early 2011, we reviewed the initial success of the RAF inhibitor vemurafenib in mutant V600 BRAF melanoma patients. It was soon evident that the response to RAF inhibitor is heterogeneous and that the short-term benefits are burdened by the development of resistance. The field has progressed rapidly with the Food and Drug Administration approval of vemurafenib and the development of other RAF and MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase) inhibitors. Despite these advances, the issue of RAF inhibitor resistance remains. Here, we review recent clinical advances in the field, the growing number of resistance mechanisms, preclinical evidence for combinatorial trials using RAF inhibitors as the building blocks, and the new challenges that are arising.