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BRAF targeted therapy changes the treatment paradigm in melanoma

Nature Reviews Clinical Oncology volume 8, pages 426–433 (2011)Cite this article

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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.

Key Points

  • BRAF is the most frequently mutated oncogene in melanoma

  • Selective BRAF inhibitors have produced tumor regression in the vast majority of patients with metastatic melanoma whose tumors harbor activating BRAF mutations

  • Selective BRAF inhibitors are associated with the appearance of keratinocyte proliferations in patients; upregulation of the MAPK pathway in normal cells observed in vitro may explain this observation

  • Additional oncogenic events are associated with BRAF mutations and may provide rational additional targets for combination therapy

  • Preliminary evidence suggests that selective BRAF inhibitors may complement immunotherapy by upregulating antigen expression but without inhibiting T-cell function

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Figure 1
Figure 2: Signal transduction through the MAP kinase pathway and the effect of BRAF inhibitors
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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles (UCLA), and the Jonsson Comprehensive Cancer Center at UCLA, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, 90095, CA, USA

    Antoni Ribas

  2. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 9E, Boston, 02114, MA, USA

    Keith T. Flaherty

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K. T. Flaherty was responsible for researching the data for this article. Both authors were involved in discussing the article content, writing the article and revising the manuscript throughout the submission process.

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Correspondence to Keith T. Flaherty.

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Competing interests

Antoni Ribas declares he is a consultant for Genentech Roche. Keith T. Flaherty declares he is a consultant for Genentech Roche and GlaxoSmithKline.

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Ribas, A., Flaherty, K. BRAF targeted therapy changes the treatment paradigm in melanoma. Nat Rev Clin Oncol 8, 426–433 (2011). https://doi.org/10.1038/nrclinonc.2011.69

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