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

摘要: IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that PARP activation consumes during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized a strategy combining biosynthesis inhibitors with alkylating chemotherapeutic agent temozolomide could potentiate depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate impact on metabolism, patient-derived xenografts and engineered IDH1-expressing cell lines were exposed to temozolomide, vitro vivo, both alone combination nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block biosynthesis. The acute time period (<3 hours) after treatment displayed burst consumption driven by activation. In IDH1-mutant-expressing cells, this reduced further abnormally lowered basal steady-state levels NAD+, introducing window hypervulnerability inhibitors. This effect was selective cells independent methylguanine methyltransferase or mismatch status, rate-limiting mediators adjuvant genotoxic sensitivity. Combined NAMPT inhibition an vivo model exhibited enhanced efficacy compared each alone. Thus, we find cancers have distinct metabolic stress responses damage regimens targeting nonredundant pathways yield potent anticancer Such convergent genetically selected minimize toxicity improve durability response therapy. Cancer Res; 77(15); 4102-15. ©2017 AACR.