title: Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair.
abstract: Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH-mutated gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas.Cancer Res; 77(7); 1709-18. ©2017 AACR.
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jakub
authors.initials: J
authors.lastname: Kwintkiewicz
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Katherine
authors.initials: K
authors.lastname: Tech
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Frady
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Su
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Wendy
authors.initials: W
authors.lastname: Bautista
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Seog In
authors.initials: SI
authors.lastname: Moon
authors.affiliation: Department of Biomedical Engineering, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: MacDonald
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Ewend
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. yangc2@mail.nih.gov.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.affiliation: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000502:physiology*; D000077204:Temozolomide
chemical_list: D010793:Phthalazines; D010879:Piperazines; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C531550:olaparib; D000077204:Temozolomide