Exth-14. the Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress and Potentiates Nad+ Depletion-mediated Cell Death in Idh1 Mutant Cancers
Year: 2017
Type: conference-abstract
Abstract: Mutant IDH1 suppresses normal IDH1 activity and alters the cellular metabolic microenvironment. We have previously identified that steady-state NAD+ level is decreased in endogenous IDH1 mutant cancers. Additionally, we found that inhibitors of the NAD+ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) potently depleted NAD+ and selectively induced cytotoxicity in IDH1 mutant cancers. Here, we investigated strategies to further perturb NAD+ metabolism to enhance NAMPT inhibitor efficacy in IDH1 mutant cancers. One major source of intracellular NAD+ consumption is mediated by distinct enzyme complexes of poly(ADP-ribose) polymerase (PARP). We found that temozolomide (TMZ), a commonly-used alkylating chemotherapeutic agent, transiently and potently reduced NAD+ to enhance NAMPT inhibitor efficacy in IDH1 mutant cancers. Mechanistically, TMZ stimulates an acute burst of NAD+ consumption by PARP via activation of DNA damage repair, and as a result, selectively potentiated NAD+ depletion-induced cytotoxicity in IDH mutant cells. In an in vivo IDH1 mutant cancer model, combined treatment with TMZ and NAMPT inhibitor enhanced efficacy compared to each agent alone. Thus, we find chemotherapy induces metabolic stress in IDH1 mutant cancers which can be exploited for therapeutic gain. Targeting of NAD+ homeostasis via convergent metabolic pathways could improve responses to metabolic therapy.
Source: Neuro-Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2768058892