EXTH-80. IMPAIRED PARP1 DNA REPAIR DEFINES CHEMO-SENSITIVITY IN IDH1-MUTATED CELL. (5th November 2018)

• Record Type: Journal Article
• Authors: Lu, Yanxin; Liu, Yang; Gilbert, Mark; Wu, Jing; Yang, Chunzhang
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi102
• Page End: vi102
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.427
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: 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 a potential therapeutic strategy by targeting PARP/BER DNA repair pathway. METHODS: We investigated transcriptomic profiles from 530 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 response to temozolomide (TMZ). Moreover, we evaluated the 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 an over 20-fold increase of cell death in IDH1 -mutated cells compared with wild type counterpart. IDH1 -mutated cells exhibited an over 1.3-fold DNA damage and a 1.42-fold increase in cellular apoptosis with 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. This suggests that their incompetence to maintain genomic integrity was 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.