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dc.contributor.authorBarker, HE
dc.contributor.authorPatel, R
dc.contributor.authorMcLaughlin, M
dc.contributor.authorSchick, U
dc.contributor.authorZaidi, S
dc.contributor.authorNutting, CM
dc.contributor.authorNewbold, KL
dc.contributor.authorBhide, S
dc.contributor.authorHarrington, KJ
dc.date.accessioned2017-04-10T15:33:52Z
dc.date.issued2016-09
dc.identifier.citationMolecular cancer therapeutics, 2016, 15 (9), pp. 2042 - 2054
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/573
dc.identifier.eissn1538-8514
dc.identifier.doi10.1158/1535-7163.mct-15-0998
dc.description.abstractHead and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitiser and investigated whether a mechanistically rational triple combination of radiation/paclitaxel/CHK1 inhibitor delivered according to an optimized schedule would provide added benefit. CCT244747 abrogated radiation-induced G2 arrest in the p53-deficient HNSCC cell lines, HN4 and HN5, causing cells to enter mitosis with unrepaired DNA damage. The addition of paclitaxel further increased cell kill and significantly reduced tumor growth in an HN5 xenograft model. Importantly, a lower dose of paclitaxel could be used when CCT244747 was included, therefore potentially limiting toxicity. Triple therapy reduced the expression of several markers of radioresistance. Moreover, the more radioresistant HN5 cell line exhibited greater radiation-mediated CHK1 activation and was more sensitive to triple therapy than HN4 cells. We analyzed CHK1 expression in a panel of head and neck tumors and observed that primary tumors from HPV(+) patients, who went on to recur postradiotherapy, exhibited significantly stronger expression of total, and activated CHK1. CHK1 may serve as a biomarker for identifying tumors likely to recur and, therefore, patients who may benefit from concomitant treatment with a CHK1 inhibitor and paclitaxel during radiotherapy. Clinical translation of this strategy is under development. Mol Cancer Ther; 15(9); 2042-54. ©2016 AACR.
dc.formatPrint-Electronic
dc.format.extent2042 - 2054
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectHead and Neck Neoplasms
dc.subjectDisease Models, Animal
dc.subjectAminopyridines
dc.subjectPaclitaxel
dc.subjectPyrimidines
dc.subjectAntineoplastic Agents
dc.subjectProtein Kinase Inhibitors
dc.subjectRadiation-Sensitizing Agents
dc.subjectCombined Modality Therapy
dc.subjectXenograft Model Antitumor Assays
dc.subjectCell Cycle
dc.subjectMitosis
dc.subjectApoptosis
dc.subjectCell Survival
dc.subjectRadiation, Ionizing
dc.subjectRadiation Tolerance
dc.subjectFemale
dc.subjectNeoplastic Stem Cells
dc.subjectChemoradiotherapy
dc.subjectCheckpoint Kinase 1
dc.titleCHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy.
dc.typeJournal Article
dcterms.dateAccepted2016-06-10
rioxxterms.versionofrecord10.1158/1535-7163.mct-15-0998
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cancer therapeutics
pubs.issue9
pubs.notes12 months
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.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-statusPublished
pubs.volume15
pubs.embargo.terms12 months
icr.researchteamTargeted Therapyen_US
dc.contributor.icrauthorBarker, Hollyen
dc.contributor.icrauthorHarrington, Kevinen
dc.contributor.icrauthorZaidi, Shane Haideren
dc.contributor.icrauthorMcLaughlin, Martinen


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