IDH1-mutant cancers are addicted to NAD+ and grow independent of 2HG levels.

  • Major finding:IDH1-mutant cancers are addicted to NAD+ and grow independent of 2HG levels.

  • Mechanism: Mutant IDH–driven reduction of NAPRT1 confers sensitivity to NAD+ depletion via NAMPT inhibition.

  • Impact: Metabolic targeting is a potential therapeutic strategy for IDH1-mutant tumors.

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2, which have been identified in multiple tumor types, result in the reduction of α-ketoglutarate (α-KG) to the α-KG analog 2-hydroxyglutarate (2HG), which has been associated with the hypermethylator phenotype of IDH-mutant cancers. Given that mutant IDH1 has also been shown to alter classical metabolic pathways, Tateishi and colleagues used a mutant IDH1–specific inhibitor (IDH1i), which inhibits 2HG formation, to perform an unbiased screen of IDH1-mutant glioma tumor-initiating cell (TIC) tumorsphere lines to identify targetable metabolic vulnerabilities. Treatment of TICs with IDH1i resulted in decreased 2HG but did not alter TIC growth or global methylation in vitro or in vivo. Short- and long-term inhibition of mutant IDH1 resulted in a significant increase of metabolites related to the NAD+/NADH shuttle system, which suggested that NAD+ was a potential therapeutic target. Consistent with this finding, IDH1-mutant TIC lines exhibited significantly lower levels of NAD+/NADH and decreased expression of a rate-limiting enzyme in the NAD+ salvage pathway, nicotinate phosphoribosyltransferase (NAPRT1), compared with IDH1–wild-type TIC lines. Furthermore, rescue experiments showed that mutant IDH1 downregulated NAPRT1, possibly by NAPRT1 promoter hypermethylation, which resulted in reduced NAD+ levels and sensitization of IDH1-mutant cells to inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another rate-limiting NAD+ salvage enzyme. Accordingly, treatment with NAMPT inhibitors resulted in a significant reduction of intracellular NAD+/NADH and cell death in IDH1/2-mutant cancer cell lines. NAMPT inhibitor–mediated NAD+ depletion resulted in the disruption of the tricarboxylic acid cycle and induction of AMP-activated protein kinase–mediated autophagy in IDH1-mutant cancer cells in vitro, and inhibited the growth of IDH1-mutant tumors in vivo. Together, these results show that IDH1 mutations promote selective addiction of cancer cells to the metabolite NAD+, resulting in a metabolic vulnerability that can be therapeutically targeted by inhibitors that are currently in clinical development.

Tateishi K, Wakimoto H, Iafrate AJ, Tanaka S, Loebel F, Lelic N, et al. Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 2015;28:773–84.

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