BRAF inhibitors for the treatment of metastatic melanoma: clinical trials and mechanisms of resistance

The efficacy of selective BRAF inhibitors has now been established in the 50% of patients with metastatic melanoma whose tumors harbor activating mutations. However, for the vast majority of patients, responses persist for less than a year. In extensive preclinical investigations, researchers have f...

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Bibliographic Details
Published inClinical cancer research Vol. 18; no. 1; pp. 33 - 39
Main Authors Alcalá, Alexander Marzuka, Flaherty, Keith T
Format Journal Article
LanguageEnglish
Published United States 01.01.2012
Subjects
Antineoplastic Agents - therapeutic use
Clinical Trials as Topic
Drug Resistance, Neoplasm
Humans
Melanoma - drug therapy
Melanoma - metabolism
Melanoma - secondary
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Signal Transduction - drug effects
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Summary:The efficacy of selective BRAF inhibitors has now been established in the 50% of patients with metastatic melanoma whose tumors harbor activating mutations. However, for the vast majority of patients, responses persist for less than a year. In extensive preclinical investigations, researchers have focused on potential resistance mechanisms with the hope of identifying treatment strategies that can overcome resistance. Preliminary results suggest that reactivation of the mitogen-activated protein kinase (MAPK) pathway by several BRAF-independent mechanisms is the predominant pattern. However, MAPK pathway-independent mechanisms also seem to play a potential role. More definitive cataloging of resistance mechanisms in patients' tumor samples is needed as combination regimens are being readied for clinical evaluation.
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ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-11-0997