Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF.

Abstract:

:Activating 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.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Haq R,Shoag J,Andreu-Perez P,Yokoyama S,Edelman H,Rowe GC,Frederick DT,Hurley AD,Nellore A,Kung AL,Wargo JA,Song JS,Fisher DE,Arany Z,Widlund HR

doi

10.1016/j.ccr.2013.02.003

subject

Has Abstract

pub_date

2013-03-18 00:00:00

pages

302-15

issue

3

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(13)00067-6

journal_volume

23

pub_type

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