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 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.
Yale School of Medicine, New Haven, Connecticut, USA.
Alexander Marzuka
AM
Alcalá
Keith T
KT
Flaherty
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf