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

Parmenter, TJ, Kleinschmidt, M, Kinross, KM, Bond, ST, Li, J, Kaadige, MR, Rao, A, Sheppard, KE, Hugo, W, Pupo, GM, Pearson, RB, McGee, SL, Long, GV, Scolyer, RA, Rizos, H, Lo, RS, Cullinane, C, Ayer, DE, Ribas, A, Johnstone, RW, Hicks, RJ and McArthur, GA 2014, Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis., Cancer Discovery, vol. 4, no. 4, pp. 423-433, doi: 10.1158/2159-8290.CD-13-0440.

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Title Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis.
Author(s) Parmenter, TJ
Kleinschmidt, M
Kinross, KM
Bond, ST
Li, J
Kaadige, MR
Rao, A
Sheppard, KE
Hugo, W
Pupo, GM
Pearson, RB
McGee, SL
Long, GV
Scolyer, RA
Rizos, H
Lo, RS
Cullinane, C
Ayer, DE
Ribas, A
Johnstone, RW
Hicks, RJ
McArthur, GA
Journal name Cancer Discovery
Volume number 4
Issue number 4
Start page 423
End page 433
Total pages 11
Publisher American Association for Cancer Research
Place of publication Philadelphia, PA
Publication date 2014-04
ISSN 2159-8290
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Oncology
METASTATIC MELANOMA
ANTITUMOR-ACTIVITY
MEK INHIBITION
RAF INHIBITOR
B-RAF
CANCER
BRAF(V600E)
METABOLISM
EXPRESSION
MUTATIONS
Summary 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 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.
Language eng
DOI 10.1158/2159-8290.CD-13-0440
Field of Research 111299 Oncology and Carcinogenesis not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, American Association for Cancer Research
Persistent URL http://hdl.handle.net/10536/DRO/DU:30067302

Document type: Journal Article
Collection: School of Medicine
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