1. Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion
- Author
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Hiroaki Wakimoto, Andrew S. Chi, Timothy He, Tracy T. Batchelor, Nina Lelic, Kensuke Tateishi, Lajos Kemény, Sudhandra Sundaram, Robert E. Gerszten, Keith T. Flaherty, Dmitri Wiederschain, Yardena Samuels, Xu Shi, Shota Tanaka, Elisabeth Roider, Fares Nigim, Olivier Bedel, Daniel P. Cahill, Franziska Loebel, Quan H Ho, A. John Iafrate, David E. Fisher, Gejing Deng, Yiyun Zhang, Dan Zhao, Mara V.A. Koerner, Jing-Ruey J. Yeh, Bailin Zhang, and William T. Curry
- Subjects
Cancer Research ,Time Factors ,Mutant ,Nicotinamide phosphoribosyltransferase ,Mice, SCID ,AMP-Activated Protein Kinases ,chemistry.chemical_compound ,0302 clinical medicine ,Tumor Cells, Cultured ,Molecular Targeted Therapy ,Enzyme Inhibitors ,Nicotinamide Phosphoribosyltransferase ,chemistry.chemical_classification ,0303 health sciences ,Brain Neoplasms ,Isocitrate Dehydrogenase ,3. Good health ,Isocitrate dehydrogenase ,Oncology ,030220 oncology & carcinogenesis ,Cytokines ,Female ,Signal Transduction ,Antineoplastic Agents ,Nicotinate phosphoribosyltransferase ,Biology ,Transfection ,Cofactor ,Glutarates ,03 medical and health sciences ,Enzyme activator ,Spheroids, Cellular ,Autophagy ,Animals ,Humans ,Metabolomics ,Pentosyltransferases ,030304 developmental biology ,Cell Proliferation ,Cell Biology ,NAD ,Molecular biology ,Xenograft Model Antitumor Assays ,Enzyme Activation ,Enzyme ,HEK293 Cells ,chemistry ,Mutation ,biology.protein ,NAD+ kinase ,Energy Metabolism ,Glioblastoma - 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.
- Published
- 2015