The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in -Mutant Cancers and Potentiates NAD Depletion-Mediated Cytotoxicity.

-mutant gliomas are dependent upon the canonical coenzyme NAD for survival. It is known that PARP activation consumes NAD during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD depletion-mediated cytotoxicity in mutant cancer cells. To investigate the impact of temozolomide on NAD metabolism, patient-derived xenografts and engineered mutant -expressing cell lines were exposed to temozolomide, and , both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD biosynthesis. The acute time period (<3 hours) after temozolomide treatment displayed a burst of NAD consumption driven by PARP activation. In -mutant-expressing cells, this consumption reduced further the abnormally lowered basal steady-state levels of NAD, introducing a window of hypervulnerability to NAD biosynthesis inhibitors. This effect was selective for -mutant cells and independent of methylguanine methyltransferase or mismatch repair status, which are known rate-limiting mediators of adjuvant temozolomide genotoxic sensitivity. Combined temozolomide and NAMPT inhibition in an -mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find -mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD pathways yield potent anticancer efficacy Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy. .