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IDH1 -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 IDH1 cancer cells. To investigate the impact of temozolomide on NAD + metabolism, patient-derived xenografts and engineered mutant IDH1 -expressing cell lines were exposed to temozolomide, in vitro and in vivo , both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD + biosynthesis. The acute time period (&lt;3 hours) after temozolomide treatment displayed a burst of NAD + consumption driven by PARP activation. In IDH1 -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 IDH1 -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 in vivo IDH1 -mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find IDH1 -mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD + pathways yield potent anticancer efficacy in vivo Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy. Cancer Res; 77(15); 4102-15. ©2017 AACR .

cancer research

The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in <i>IDH1</i>-Mutant Cancers and Potentiates NAD+ Depletion–Mediated Cytotoxicity

The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1-Mutant Cancers and Potentiates NAD+ Depletion–Mediated Cytotoxicity