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Clin Cancer Res. 2012 Jan 1;18(1):33-9. doi: 10.1158/1078-0432.CCR-11-0997.

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

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Yale School of Medicine, New Haven, Connecticut, USA.


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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