Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion.

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.

• Authors: Kensuke Tateishi, Hiroaki Wakimoto, A John Iafrate, Shota Tanaka, Franziska Loebel, Nina Lelic, Dmitri Wiederschain, Olivier Bedel, Gejing Deng, Bailin Zhang, Timothy He, Xu Shi, Robert E Gerszten, Yiyun Zhang, Jing-Ruey J Yeh, William T Curry, Dan Zhao, Sudhandra Sundaram, Fares Nigim, Mara V A Koerner, Quan Ho, David E Fisher, Elisabeth M Roider, Lajos V Kemeny, Yardena Samuels, Keith T Flaherty, Tracy T Batchelor, Andrew S Chi, Daniel P Cahill
• Journal: Cancer cell (Cancer Cell) Vol. 28 Issue 6 Pg. 773-784 (Dec 14 2015) ISSN: 1878-3686 [Electronic] United States
• PMID: 26678339 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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