Date: 16 Jun 2017
IDH1-mutant gliomas are dependent upon the canonical coenzyme nicotinamide adenine dinucleotide (NAD+) for survival. It is known that Poly(ADP-ribose) polymerase (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 (TMZ) could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of TMZ on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to TMZ, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis. The acute time-period (<3 hrs) after TMZ 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 hyper-vulnerability to NAD+ biosynthesis inhibitors. This effect was selective for IDH1-mutant cells and independent of methylguanine methyltransferase (MGMT) or mismatch repair (MMR) status, which are known rate-limiting mediators of adjuvant TMZ genotoxic sensitivity. Combined TMZ and NAMPT inhibition in an in vivo IDH1-mutant cancer model exhibited enhanced efficacy compared to each agent alone. Thus, we find IDH1-mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting non-redundant NAD+ pathways yield potent anti-cancer efficacy in vivo. Such targeting of convergent metabolic pathways in genetically-selected cancers could minimize treatment toxicity and improve durability of response to therapy.
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Kensuke Tateishi, M.D., Ph.D.
E-mail: email@example.com Phone: +81 45 787 2663
Assistant Professor of Neurosurgery,
Yokohama City University, Graduate School of Medicine
Fukuura 3-9, Kanazawa-ku, Yokohama, 236-0004 JAPAN