BRAF Targeted Therapy Changes the Treatment Paradigm in Melanoma

Antoni Ribas; Keith T. Flaherty

Nat Rev Clin Onc. 2011;8(7)

Abstract and Introduction

Abstract

After decades of stagnation, recent therapeutic advances in melanoma seem on the horizon. The discovery of the genetic underpinnings of this historically refractory disease has exposed potential targets for therapy, BRAF mutations being principal among them. In the 8 years following the discovery of BRAF mutations in 50–60% of advanced melanomas, only recently have potent and selective inhibitors of this intracellular signaling molecule shown efficacy from early clinical testing. Vemurafenib (PLX4032) and GSK2118436, two orally available and well tolerated agents are on the verge of transforming the landscape of melanoma therapy based on the promising results of their respective phase I, II, and III trials.

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Box 1. Class I and II RAF inhibitors
Class I RAF inhibitors include vemurafenib (PLX4032/RG7204) and GSK2118436 and are active against the activated form of the RAF kinases Class II RAF inhibitors, such as sorafenib, inhibit the resting conformation of the kinase, with very low activity against BRAFV600E mutant cancer cells in humans

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