Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis

Tiffany J. Parmenter, Margarete Kleinschmidt, Kathryn M. Kinross, Simon T. Bond, Jason Li, Mohan R. Kaadige, Aparna Rao, Karen E. Sheppard, Willy Hugo, Gulietta M. Pupo, Richard B. Pearson, Sean L. McGee, Georgina V. Long, Richard A. Scolyer, Helen Rizos, Roger S. Lo, Carleen Cullinane, Donald E. Ayer, Antoni Ribas, Ricky W. Johnstone & 2 others Rodney J. Hicks, Grant A. McArthur

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Deregulated glucose metabolism fulfills 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 benefit in BRAF -mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF -mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAFV600, 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 benefit in BRAFV600 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.

Original languageEnglish
Pages (from-to)423-433
Number of pages11
JournalCancer Discovery
Volume4
Issue number4
DOIs
Publication statusPublished - Apr 2014
Externally publishedYes

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    Parmenter, T. J., Kleinschmidt, M., Kinross, K. M., Bond, S. T., Li, J., Kaadige, M. R., ... McArthur, G. A. (2014). Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discovery, 4(4), 423-433. https://doi.org/10.1158/2159-8290.CD-13-0440