Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF

SummaryActivating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecules leads to cell-cycle arrest and apoptosis. We show here that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1α. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1α. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1α and decreased oxidative metabolism. Conversely, treatment of BRAF-mutated melanomas with BRAF inhibitors renders them addicted to oxidative phosphorylation. Our data thus identify an adaptive metabolic program that limits the efficacy of BRAF inhibitors.

► BRAF suppresses mitochondrial density and oxidative phosphorylation metabolism ► MITF directly regulates the mitochondrial biogenesis factor, PGC1α ► Melanomas with activation of the MAPK pathway have lower levels of MITF and PGC1α ► Mitochondrial uncouplers may have therapeutic use in combination with BRAF inhibitors