Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

PLX4032, a small-molecule inhibitor being developed by Plexxikon of California and Roche Pharmaceuticals in New Jersey (http://go.nature.com/QnVGQx), selectively targets B-RAFV600E, a mutant form of the B-RAF protein kinase common in several human cancers. In this issue of Nature, Gideon Bollag and colleagues report promising results for PLX4032 in an early clinical trial in melanoma patients who carry this B-RAF mutation. They also describe the structure and function of PLX4032 and present translational data from a phase I trial to show that clinical efficacy requires a drug concentration that is sufficient to cause a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The study demonstrates how the design of early clinical trials based on the biological mechanisms underlying tumour formation has the potential to speed up the process by which anticancer drugs can reach the clinic.