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Cancer Cell. 2015 Dec 14;28(6):773-84. doi: 10.1016/j.ccell.2015.11.006.

Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion.

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  • 1Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 2Department of Pathology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 3Divisions of Neuro-Oncology and Hematology/Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 4Sanofi Oncology, Cambridge, MA 02139, USA.
  • 5Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 6Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 7Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 8Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 9Divisions of Neuro-Oncology and Hematology/Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: chia01@nyumc.org.
  • 10Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: cahill@mgh.harvard.edu.

Abstract

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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PMID:
26678339
PMCID:
PMC4684594
DOI:
10.1016/j.ccell.2015.11.006
[PubMed - indexed for MEDLINE]
Free PMC Article

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