Summary 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.

Background: Mutant-selective IDH1 inhibitors are potential cancer therapeutics, but the mechanistic basis for their selectivity is not yet well understood. Results: Inhibitor binding modes and kinetic mechanisms were characterized. Conclusion:The inhibitors selectively inhibit mutant IDH1 by interacting with a magnesium-binding residue. Significance: Targeting metal-binding residues with drug-like small molecules is a feasible strategy for IDH1 inhibition.

No abstract