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Mutations in IDH1 or IDH2 characterize the majority of diffuse infiltrative gliomas of younger adulthood. DNA alkylator chemotherapy has proven to be an effective treatment for IDH mutant glioma, yet recurrences remain frequent and improved treatments are needed. Upon exposure of cancer cells to DNA alkylating agents, poly(ADP-ribose) polymerases (PARPs) catalyze the transient oligomerization of nicotinamide adenine dinucleotide (NAD+) into poly-ADP-ribose (PAR) chain-assemblies, which stimulate the DNA damage response. Here, we find that, in IDH mutant glioma cells, alkylator-induced cytotoxicity is dramatically augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme poly(ADP-ribose) glycohydrolase (PARG). Mechanistically, we show this augmentation is driven by a metabolic state pairing amplified alkylator-induced DNA damage with catastrophic depletion of NAD+. IDH mutant cancer cells have low basal levels of NAD+, rendering them vulnerable to prolonged NAD+ depletion. Either of two clinically-utilized monofunctional alkylators, procarbazine (PCZ) or temozolomide (TMZ), when exposed to multiple IDH mutant lines, activated PARP conversion of cellular NAD+ monomers into polymerized PAR. Subsequent PAR breakdown and recycling of NAD+ monomers was then halted by concomitant PARG inactivation, amplifying PARylation-mediated DNA damage signaling and critically depleting free NAD+, resulting in profound cytotoxicity. This effect was partially reversed by NAD+ rescue supplementation, confirming the key contribution of metabolic stress. Combined alkylator treatment and PARG inhibition in vivo maximized both NAD+ depletion and cytotoxicity in an endogenous IDH mutant cancer model. Thus, alkyating DNA damaging agents expose a metabolic liability in IDH mutant cancers, and subsequent targeted blockade of PAR breakdown and NAD+ metabolite recovery can exploit this vulnerability to provide genotype-specific therapeutic benefit.

neuro-oncology

TAMI-20. POLY(ADP-RIBOSE) GLYCOHYDROLASE INHIBITION SEQUESTERS NAD+ TO POTENTIATE THE METABOLIC LETHALITY OF ALKYLATING CHEMOTHERAPY IN IDH MUTANT TUMOR CELLS