Title |
Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion
|
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Published in |
Cancer Cell, December 2015
|
DOI | 10.1016/j.ccell.2015.11.006 |
Pubmed ID | |
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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 12 | 43% |
Guinea | 1 | 4% |
Brazil | 1 | 4% |
Saudi Arabia | 1 | 4% |
Japan | 1 | 4% |
Portugal | 1 | 4% |
France | 1 | 4% |
Ireland | 1 | 4% |
Canada | 1 | 4% |
Other | 1 | 4% |
Unknown | 7 | 25% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 16 | 57% |
Scientists | 8 | 29% |
Science communicators (journalists, bloggers, editors) | 3 | 11% |
Practitioners (doctors, other healthcare professionals) | 1 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 3 | <1% |
United States | 3 | <1% |
Spain | 2 | <1% |
Japan | 2 | <1% |
Denmark | 1 | <1% |
Sweden | 1 | <1% |
Unknown | 324 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 68 | 20% |
Researcher | 65 | 19% |
Student > Master | 36 | 11% |
Student > Bachelor | 30 | 9% |
Other | 18 | 5% |
Other | 70 | 21% |
Unknown | 49 | 15% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 90 | 27% |
Agricultural and Biological Sciences | 61 | 18% |
Medicine and Dentistry | 51 | 15% |
Pharmacology, Toxicology and Pharmaceutical Science | 19 | 6% |
Neuroscience | 9 | 3% |
Other | 44 | 13% |
Unknown | 62 | 18% |