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dc.contributor.authorHafsi, Hen_US
dc.contributor.authorDillon, MTen_US
dc.contributor.authorBarker, HEen_US
dc.contributor.authorKyula, JNen_US
dc.contributor.authorSchick, Uen_US
dc.contributor.authorPaget, JTen_US
dc.contributor.authorSmith, HGen_US
dc.contributor.authorPedersen, Men_US
dc.contributor.authorMcLaughlin, Men_US
dc.contributor.authorHarrington, KJen_US
dc.date.accessioned2018-07-18T15:19:46Z
dc.date.issued2018-01en_US
dc.identifier.citationFrontiers in oncology, 2018, 8 pp. 245 - ?en_US
dc.identifier.issn2234-943Xen_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2093
dc.identifier.eissn2234-943Xen_US
dc.identifier.doi10.3389/fonc.2018.00245en_US
dc.description.abstractHead and neck squamous cell carcinoma (HNSCC) is a significant cause of cancer deaths. Cisplatin-based chemoradiotherapy is a standard of care for locally advanced disease. ATR and DNA-PK inhibition (DNA-PKi) are actively being investigated in clinical trials with preclinical data supporting clinical translation as radiosensitizers. Here, we hypothesized that targeting both ATR and DNA-PK with small molecule inhibitors would increase radiosensitization of HNSCC cell lines. Radiosensitization was assessed by Bliss independence analysis of colony survival data. Strong cell cycle perturbing effects were observed with ATR inhibition reversing the G2/M arrest observed for radiation-DNA-PKi. Increased apoptosis in combination groups was measured by Sub-G1 DNA populations. DNA-PKi increased radiation-induced RAD51 and gamma-H2Ax foci, with the addition of ATR inhibition reducing levels of both. A sharp increase in nuclear fragmentation after aberrant mitotic transit appears to be the main driver of decreased survival due to irradiation and dual ATR/DNA-PKi. Dual inhibition of DNA-PK and ATR represents a novel approach in combination with radiation, with efficacy appearing to be independent of p53 status. Due to toxicity concerns, careful assessment is necessary in any future translation of single or dual radiosensitization approaches. Ongoing clinical trials into the ATR inhibitor AZD6738 plus radiation, and the phenotypically similar combination of AZD6738 and the PARP inhibitor olaparib, are likely to be key in ascertaining the toxicity profile of such combinations.en_US
dc.formatElectronic-eCollectionen_US
dc.format.extent245 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleCombined ATR and DNA-PK Inhibition Radiosensitizes Tumor Cells Independently of Their p53 Status.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-06-18en_US
rioxxterms.versionofrecord10.3389/fonc.2018.00245en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2018-01en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfFrontiers in oncologyen_US
pubs.notesNo embargoen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.publication-statusPublisheden_US
pubs.volume8en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamTargeted Therapyen_US
dc.contributor.icrauthorMcLaughlin, Martinen_US
dc.contributor.icrauthorDillon, Magnusen_US
dc.contributor.icrauthorSmith, Henryen_US
dc.contributor.icrauthorPedersen, Malinen_US
dc.contributor.icrauthorHarrington, Kevinen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/