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Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis
journal contribution
posted on 2014-04-01, 00:00 authored by T J Parmenter, M Kleinschmidt, K M Kinross, Simon Bond, J Li, M R Kaadige, A Rao, K E Sheppard, W Hugo, G M Pupo, R B Pearson, Sean McgeeSean Mcgee, G V Long, R A Scolyer, H Rizos, R S Lo, C Cullinane, D E Ayer, A Ribas, R W Johnstone, R J Hicks, G A McArthurDeregulated 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 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.
History
Journal
Cancer DiscoveryVolume
4Issue
4Pagination
423 - 433Publisher
American Association for Cancer ResearchLocation
Philadelphia, PAPublisher DOI
ISSN
2159-8290eISSN
2159-8290Language
EnglishPublication classification
C Journal article; C1 Refereed article in a scholarly journalCopyright notice
2014, American Association for Cancer ResearchUsage metrics
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