title: Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells.
abstract: Glioblastoma-initiating cells (GICs) are self-renewing tumorigenic sub-populations, contributing to therapeutic resistance via decreased sensitivity to ionizing radiation (IR). GIC survival following IR is attributed to an augmented response to genotoxic stress. We now report that GICs are primed to handle additional stress due to basal activation of single-strand break repair (SSBR), the main DNA damage response pathway activated by reactive oxygen species (ROS), compared with non-GICs. ROS levels were higher in GICs and likely contributed to the oxidative base damage and single-strand DNA breaks found elevated in GICs. To tolerate constitutive DNA damage, GICs exhibited a reliance on the key SSBR mediator, poly-ADP-ribose polymerase (PARP), with decreased viability seen upon small molecule inhibition to PARP. PARP inhibition (PARPi) sensitized GICs to radiation and inhibited growth, self-renewal, and DNA damage repair. In vivo treatment with PARPi and radiotherapy attenuated radiation-induced enrichment of GICs and inhibited the central cancer stem cell phenotype of tumor initiation. These results indicate that elevated PARP activation within GICs permits exploitation of this dependence, potently augmenting therapeutic efficacy of IR against GICs. In addition, our results support further development of clinical trials with PARPi and radiation in glioblastoma.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave NE30 9500 Euclid Ave, Cleveland, OH 44195, USA.
authors.forename: M
authors.initials: M
authors.lastname: Venere
authors.affiliation: 1] Genome Integrity Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark [2] Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, Olomouc CZ-775 15, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Hamerlik
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave NE30 9500 Euclid Ave, Cleveland, OH 44195, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Genome Integrity Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
authors.forename: R D
authors.initials: RD
authors.lastname: Rasmussen
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave NE30 9500 Euclid Ave, Cleveland, OH 44195, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Song
authors.affiliation: ImageIQ Inc., Cleveland, OH 44106, USA.
authors.forename: A
authors.initials: A
authors.lastname: Vasanji
authors.affiliation: ImageIQ Inc., Cleveland, OH 44106, USA.
authors.forename: N
authors.initials: N
authors.lastname: Tenley
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave NE30 9500 Euclid Ave, Cleveland, OH 44195, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Flavahan
authors.affiliation: 1] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave NE30 9500 Euclid Ave, Cleveland, OH 44195, USA [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Hjelmeland
authors.affiliation: 1] Genome Integrity Unit, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark [2] Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, Olomouc CZ-775 15, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Bartek
authors.affiliation: 1] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave NE30 9500 Euclid Ave, Cleveland, OH 44195, USA [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib