Abstract 2993: Impaired PARP1 DNA repair defines chemo-sensitivity in IDH1 mutant cell

Abstract

Abstract INTRODUCTION: Mutations in isocitrate dehydrogenase (IDH1/2) are the most prevalent genetic deficiency in lower grade gliomas. IDH-mutated in glioma exhibits better clinical outcomes with longer patient survival, as well as greater sensitivity to chemotherapy. In the present study, we explored the molecular mechanisms that determine the chemo-sensitivity in IDH1-mutated cells, and seek for potential therapeutic strategy by targeting PARP/BER DNA repair pathway. METHODS: We investigated transcriptomic profile from WHO grade II/III glioma based on their IDH1/2 mutation status. We established IDH1-mutated cells and investigated the alterations in nicotinamide adenine dinucleotide (NAD+), Poly (ADP-ribose) polymerase (PARP)-associated DNA repair and DNA damage in these cells in respond to temozolomide (TMZ). Moreover, we evaluated a PARP inhibitor olaparib and its synergistic effect on TMZ-associated cytotoxicity. RESULTS: Our results showed that the IDH1-mutated cells are more vulnerable to genotoxic agent, which recapitulate the disease phenotype in IDH1-mutated glioma. TMZ treatment resulted in over 20-fold increase of cell death in IDH1-mutated cells compared with wild type counterpart. IDH1-mutated cells exhibited over 1.3-fold DNA damage and over 1.42-fold cellular apoptosis under TMZ treatment. Mechanistically, IDH1-mutated cells exhibited compromised NAD+ metabolism, as well as concomitant PARP/BER DNA repair pathway. IDH1-mutated cells produced 83.8% less poly (ADP-ribose) polymer (pADPR), an important substrate for PARP-associated DNA repair, during TMZ treatment, suggesting their incompetence to maintain genomic integrity due to decreased availability of NAD+. Targeting the PARP-associated DNA repair pathway using olaparib, an FDA-approved PARP inhibitor, remarkably potentiated TMZ-induced cytotoxic effects by 2.16-fold in IDH1-mutated cells. CONCLUSION: Our findings demonstrate that metabolic defects in IDH1-mutated cells affect PARP-associated DNA repair pathway via NAD+ depletion, and therefore prompt the sensitivity to chemotherapies. Targeting PARP-associated DNA repair pathway suggests a novel therapeutic avenue for IDH1-mutated gliomas. Citation Format: Chunzhang Yang, Yanxin Lu, Yang Liu, Mark Gilbert, Jing Wu. Impaired PARP1 DNA repair defines chemo-sensitivity in IDH1 mutant cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2993.