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


CONCLUSIONS
BRAF is 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.
1Molecular Oncology Laboratory, Oncogenic Signaling and Growth Control Program, 2Translational Research Laboratory, Cancer Therapeutics Program, 3Bioinformatics Core Facility, 4The Cancer Signalling Laboratory, Oncogenic Signaling and Growth Control Program, 5Gene Regulation Laboratory, Cancer Therapeutics Program, 6Molecular Imaging and Targeted Therapeutics Laboratory, Cancer Therapeutics Program, 7Department of Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne; 8Sir Peter MacCallum Department of Oncology, Departments of 9Biochemistry and Molecular Biology, and 10Pathology, University of Melbourne, Parkville; 11Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds; 12Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria; 13Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead; 14Department of Tissue Pathology & Diagnostic Oncology, Royal Prince Alfred Hospital; 15Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia; 16Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; and 17Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.
Tiffany J
TJ
Parmenter
Margarete
M
Kleinschmidt
Kathryn M
KM
Kinross
Simon T
ST
Bond
Jason
J
Li
Mohan R
MR
Kaadige
Aparna
A
Rao
Karen E
KE
Sheppard
Willy
W
Hugo
Gulietta M
GM
Pupo
Richard B
RB
Pearson
Sean L
SL
McGee
Georgina V
GV
Long
Richard A
RA
Scolyer
Helen
H
Rizos
Roger S
RS
Lo
Carleen
C
Cullinane
Donald E
DE
Ayer
Antoni
A
Ribas
Ricky W
RW
Johnstone
Rodney J
RJ
Hicks
Grant A
GA
McArthur
D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000077484:Vemurafenib
D007211:Indoles; C528407:PLX 4720; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D014157:Transcription Factors; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C500026:palbociclib