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Selective inhibition of parallel DNA damage response pathways optimizes radiosensitization of glioblastoma stem-like cells

Ahmed, Shafiq, Carruthers, R, Gilmour, L, Yildirim, S, Watts, C and Chalmers, A (2015) Selective inhibition of parallel DNA damage response pathways optimizes radiosensitization of glioblastoma stem-like cells. Cancer Research, 75 (20). pp. 4416-4428. ISSN 0008-5472

Item Type: Article

Abstract

Glioblastoma is the most common form of primary brain tumor in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and is thought to be driven by glioblastoma stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived glioblastoma cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP1 were upregulated in GSCs, and CHK1 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G2-M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G2-M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of CHK1, ATR, or PARP alone. Combined inhibition of PARP and ATR resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC.

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Depositing User: Paula Normington

Identifiers

Item ID: 6004
Identification Number: https://doi.org/10.1158/0008-5472.CAN-14-3790
ISSN: 0008-5472
URI: http://sure.sunderland.ac.uk/id/eprint/6004
Official URL: http://cancerres.aacrjournals.org/content/early/20...

Users with ORCIDS

ORCID for Shafiq Ahmed: ORCID iD orcid.org/0000-0001-8701-6889

Catalogue record

Date Deposited: 12 Feb 2016 10:22
Last Modified: 18 Dec 2019 15:38

Contributors

Author: Shafiq Ahmed ORCID iD
Author: R Carruthers
Author: L Gilmour
Author: S Yildirim
Author: C Watts
Author: A Chalmers

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences

Subjects

Sciences

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