BRAF targeted therapy changes the treatment paradigm in melanoma

Therapeutic advances in melanoma seem on the horizon, with the identification of BRAF as a principal therapeutic target. The authors describe the scientific basis for the targeting of BRAF mutations in cancer, the early clinical data with BRAF inhibitors, and how combinatorial therapies may address...

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Published in:Nature reviews. Clinical oncology Vol. 8; no. 7; pp. 426 - 433
Main Authors: Ribas, Antoni, Flaherty, Keith T.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.07.2011
Nature Publishing Group
Subjects:
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692/699/67/1813/1634
Cancer
Chemotherapy
Diagnosis
Drug therapy
Gene mutations
Genetic aspects
Health aspects
Humans
Indoles - therapeutic use
Medicine
Medicine & Public Health
Melanoma
Melanoma - drug therapy
Melanoma - genetics
Methods
Mutation - genetics
Oncology
Proto-Oncogene Proteins B-raf - genetics
review-article
Sulfonamides - therapeutic use
United States
ISSN:1759-4774, 1759-4782, 1759-4782
Online Access:Get full text
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Summary:Therapeutic advances in melanoma seem on the horizon, with the identification of BRAF as a principal therapeutic target. The authors describe the scientific basis for the targeting of BRAF mutations in cancer, the early clinical data with BRAF inhibitors, and how combinatorial therapies may address the current limitations of their use in the clinic. 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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ISSN:1759-4774
1759-4782
1759-4782
DOI:10.1038/nrclinonc.2011.69