Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion
Open accessAbstract
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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Mutant IDH inhibitors may not be effective in all IDH-mutant cancers; in many IDH-mutant glioma models they fail to reverse epigenetic changes or inhibit tumor proliferation despite lowering 2-HG.
“Despite success in some preclinical models and patients with AML, mutant IDH inhibitors may not be effective in all IDH-mutant cancers. For example, these drugs are unable to reverse epigenetic changes or inhibit tumor proliferation in many models of IDH mutant glioma, despite a robust ability to lower 2-HG in cells and tumors (Tateishi et al., 2015; Turcan et al., 2013).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Tateishi et al., 2015
Tumors harboring an IDH mutation have increased sensitivity to hypomethylating agents, electron transport chain inhibitors, depletion of NAD+, and chemoradiotherapy.
“For example, tumors harboring an IDH mutation have increased sensitivity to hypomethylating agents (Turcan et al., 2013), electron transport chain inhibitors (Grassian et al., 2014), depletion of the coenzyme NAD+ (Tateishi et al., 2015) and chemoradiotherapy (Cairncross et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Tateishi et al., 2015
Sensitivity to mutant IDH inhibitors appears to differ between leukemia and solid tumor models.
“Even among cancers where mutant IDH is an oncogenic driver, sensitivity to mutant IDH inhibitors appears to differ between leukemia and solid tumor models (Tateishi et al., 2015; Turcan et al., 2013).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Tateishi et al., 2015
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- Authors
- Tateishi, K., Wakimoto, H., Iafrate, A. J., Tanaka, S., Loebel, F., Lelic, N., Wiederschain, D., Bedel, O., Deng, G., Zhang, B., He, T., Shi, X., Gerszten, R. E., Zhang, Y., Yeh, J.-R. J., Curry, W. T., Zhao, D., Sundaram, S., Nigim, F., Koerner, M. V. A., Ho, Q., Fisher, D. E., Roider, E. M., Kemeny, L. V., Samuels, Y., Flaherty, K. T., Batchelor, T. T., Chi, A. S., & Cahill, D. P.
- Affiliations
- Harvard University (US)
- Weizmann Institute of Science (IL)
- Corresponding author
- Chi, Andrew S.
- Cahill, Daniel P.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 28
- Issue
- 6
- Pages
- 773-784
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4684594
- OpenAlex
- W2192221936
- Cited by
- 433
- References
- 64
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 47 · 2023: 50 · 2022: 42 · 2021: 49 · 2020: 52 · 2019: 42 · 2018: 45 · 2017: 35 · 2016: 21
- FWCI
- 11.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (NIHP50CA165962-01A1, NIH R01CA140188, NIH K24 CA125440-06, R01CA140188, K24CA125440, P50CA165962)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR043369)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- IDH1 mutation, NAD+ depletion, 2-hydroxyglutarate, NAD+ salvage pathway, NAMPT inhibition, AMPK activation, autophagy, cancer metabolism, metabolic vulnerability, solid tumors
- MeSH terms
- Animals, Antineoplastic Agents, Autophagy, Brain Neoplasms, Energy Metabolism, Enzyme Activation, Enzyme Inhibitors, Female, Glioblastoma, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, NAD, Pentosyltransferases, Time Factors, Transfection, Tumor Cells, Cultured, Signal Transduction, Cytokines, Mice, SCID, Spheroids, Cellular, Xenograft Model Antitumor Assays, Cell Proliferation, Nicotinamide Phosphoribosyltransferase, AMP-Activated Protein Kinases, Metabolomics, HEK293 Cells, Molecular Targeted Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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