Response of BRAF -Mutant Melanoma to BRAF Inhibition Is Mediated by a Network of

Deregulated glucose metabolism fulfi lls the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefi t in BRAF -mutant melanoma, we exam- ined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consist- ent decreases in glycolytic activity in BRAF -mutant melanoma cells. Moreover, we identifi ed a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably , this network of transcription factors, including hypoxia-inducible factor-1 α, MYC, and MONDOA (MLXIP), drives gly- colysis downstream of BRAF V600 , is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)-resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors. SIGNIFICANCE: BRAFis suppress glycolysis and provide strong clinical benefi t in BRAF V600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors. Cancer Discov; 4(4); 1-11. ©2014 AACR.