Abstract 4969: Impaired PARP1 DNA repair defines chemosensitivity in IDH1 mutant cell

Abstract

Abstract INTRODUCTION: Mutations in isocitrate dehydrogenase (IDH1/2) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of IDH mutations in glioma are prognostic for better clinical outcomes with longer patient survival, and greater sensitivity to chemotherapy. In the present study, we explore the molecular mechanisms that determine the chemosensitivity in IDH1-mutated glioma cells, and seek a potential therapeutic strategy by targeting DNA repair pathway in IDH1-mutated cells. METHODS: We established IDH1-mutated cell lines by introducing pathogenic IDH1 mutations into glioma cells via lentivirus. We confirmed the metabolic deficiency and enhanced chemosensitivity in cells expressing IDH1 mutant enzyme. Further, we measured the intracellular level of nicotinamide adenine dinucleotide (NAD+), Poly (ADP-ribose) polymerase (PARP)-associated DNA repair and DNA damage level in these cells when treated with temozolomide (TMZ). Moreover, we evaluated a PARP inhibitor Olaparib and its synergic effect on TMZ-associated cytotoxicity. RESULTS: Our results show that the IDH1-mutated cells are more vulnerable to chemotherapy. TMZ treatment resulted in over 20-fold increase of cell death in IDH1-mutated cells compared with their wild type counterpart. IDH1-mutated cells exhibited an over 1.3-fold increase in DNA damage and over 1.42-fold increase in cellular apoptosis under TMZ treatment. Accordingly, 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 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 may represent a novel therapeutic avenue for IDH1-mutated gliomas. Citation Format: Yanxin Lu, Yang Liu, Yu-Ting Su, Wendy Bautista, Mark R. Gilbert, Jing Wu, Chunzhang Yang. Impaired PARP1 DNA repair defines chemosensitivity in IDH1 mutant cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4969. doi:10.1158/1538-7445.AM2017-4969