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

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 (<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.