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.

] 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

] 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

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

Genome Integrity Unit Danish Cancer Society Research Center Strandboulevarden 49 Copenhagen DK 2100 Denmark

ImageIQ Inc Cleveland OH 44106 USA

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Cell Death Differ. 2014 Feb;21(2):192-3. doi: 10.1038/cdd.2013.172. PubMed

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