Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion

• Growth of IDH1 mutant cancers can be decoupled from 2-hydroxyglutarate levels
• Mutant IDH1 decreases NAD+ levels by inhibiting an alternate NAD+ salvage pathway
• Depletion of NAD+ is strikingly potent and specific for IDH1 mutant cancers
• NAD+ depletion induces autophagy by activating intracellular energy sensors

SummaryHeterozygous 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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