Journal
CANCER CELL
Volume 28, Issue 6, Pages 773-784Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2015.11.006
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Funding
- Richard B. Simches Scholars Award
- MGH Glioblastoma Research Fund
- Burroughs Wellcome Fund Career Award
- NIH [P50CA165962-01A1, K24 CA125440-06, R01CA140188]
- Society of Nuclear Medicine and Molecular Imaging Wagner-Torizuka Fellowship
- Japan Brain Foundation
- American Heart Association Established Investigator Award
- MGH Cardiology Hassenfeld Scholar Award
- KANAE Foundation for the Promotion of Medical Science
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Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers.
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