Molecular Pathways Molecular Pathways : BRAF Induces Bioenergetic Adaptation by Attenuating Oxidative Phosphorylation

Cancers acquire mutations in cooperating pathways that sustain their growth and survival. To support continued proliferation, tumor cells adapt their metabolism to balance energy production with their augmented biosynthetic needs. Although most normal differentiated cells use mitochondrial oxidative phosphorylation (OXPHOS) as the bioenergetic source, cancer cells have been proposed to rely principally on cytoplasmic glycolysis. The molecular basis for this shift, termed the Warburg effect, is the subject of intense investigation, because mechanistic understanding may lead to novel approaches to target the altered metabolism of cancer cells. Recently, mutations BRAF(V600E) have emerged as a major regulator of metabolic homeostasis. Melanoma cells may use a metabolic shift to circumvent BRAF(V600E)-induced senescence though limiting their reliance on OXPHOS and promote proliferation. Furthermore, BRAF(V600E) acts to suppress expression of the melanocyte master regulator microphthalmia-associated transcription factor (MITF) and the mitochondrial biogenesis coactivator PGC1α. Accordingly, therapeutic inhibition of BRAF(V600E) reverses metabolic reprogramming in melanoma cells and elevates OXPHOS through increased MITF–PGC1α levels. BRAF-targeted drugs modulate the metabolic state of malignant melanoma cells, and counteracting these adaptive responses using pharmacologic agents may prove useful in combinatorial therapeutic strategies. Clin Cancer Res; 20(9); 2257–63. ©2014 AACR.