Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion

Cancer Cell. 2015 Dec 14;28(6):773-784. doi: 10.1016/j.ccell.2015.11.006.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Autophagy / drug effects
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Cytokines / antagonists & inhibitors*
  • Cytokines / metabolism
  • Energy Metabolism / drug effects
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / enzymology
  • Glioblastoma / genetics
  • Glioblastoma / pathology
  • Glutarates / metabolism
  • HEK293 Cells
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Metabolomics / methods
  • Mice, SCID
  • Molecular Targeted Therapy
  • Mutation*
  • NAD / deficiency*
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Pentosyltransferases / metabolism
  • Signal Transduction / drug effects
  • Spheroids, Cellular
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cytokines
  • Enzyme Inhibitors
  • Glutarates
  • NAD
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Pentosyltransferases
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human
  • AMP-Activated Protein Kinases
  • nicotinate phosphoribosyltransferase

Associated data

  • GEO/GSE73270