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dc.contributor.authorMcLaughlin, Men_US
dc.contributor.authorBarker, HEen_US
dc.contributor.authorKhan, AAen_US
dc.contributor.authorPedersen, Men_US
dc.contributor.authorDillon, Men_US
dc.contributor.authorMansfield, DCen_US
dc.contributor.authorPatel, Ren_US
dc.contributor.authorKyula, JNen_US
dc.contributor.authorBhide, SAen_US
dc.contributor.authorNewbold, KLen_US
dc.contributor.authorNutting, CMen_US
dc.contributor.authorHarrington, KJen_US
dc.coverage.spatialEnglanden_US
dc.date.accessioned2017-02-28T11:58:20Z
dc.date.issued2017-01-31en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/28143445en_US
dc.identifier10.1186/s12885-017-3084-0en_US
dc.identifier.citationBMC Cancer, 2017, 17 (1), pp. 86 - ?en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/409
dc.identifier.eissn1471-2407en_US
dc.identifier.doi10.1186/s12885-017-3084-0en_US
dc.description.abstractBACKGROUND: Concurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT is frequently ineffective in patients with advanced disease. It has previously been shown that HSP90 inhibitors act as radiosensitizers, but these studies have not focused on CCRT in HNSCC. Here, we evaluated the HSP90 inhibitor, AUY922, combined with CCRT. METHODS: The ability of AUY922 to sensitize to CCRT was assessed in p53 mutant head and neck cell lines by clonogenic assay. Modulation of the CCRT induced DNA damage response (DDR) by AUY922 was characterized by confocal image analysis of RAD51, BRCA1, 53BP1, ATM and mutant p53 signaling. The role of FANCA depletion by AUY922 was examined using shRNA. Cell cycle checkpoint abrogation and chromosomal fragmentation was assessed by western blot, FACS and confocal. The role of ATM was also assessed by shRNA. AUY922 in combination with CCRT was assessed in vivo. RESULTS: The combination of AUY922 with cisplatin, radiation and CCRT was found to be synergistic in p53 mutant HNSCC. AUY922 leads to significant alterations to the DDR induced by CCRT. This comprises inhibition of homologous recombination through decreased RAD51 and pS1524 BRCA1 with a corresponding increase in 53BP1 foci, activation of ATM and signaling into mutant p53. A shift to more error prone repair combined with a loss of checkpoint function leads to fragmentation of chromosomal material. The degree of disruption to DDR signalling correlated to chromosomal fragmentation and loss of clonogenicity. ATM shRNA indicated a possible rationale for the combination of AUY922 and CCRT in cells lacking ATM function. CONCLUSIONS: This study supports future clinical studies combining AUY922 and CCRT in p53 mutant HNSCC. Modulation of the DDR and chromosomal fragmentation are likely to be analytical points of interest in such trials.en_US
dc.format.extent86 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectATMen_US
dc.subjectAUY922en_US
dc.subjectDDRen_US
dc.subjectFANCAen_US
dc.subjectHNSCCen_US
dc.subjectRAD51en_US
dc.subjectAnimalsen_US
dc.subjectBRCA1 Proteinen_US
dc.subjectCarcinoma, Squamous Cellen_US
dc.subjectCell Line, Tumoren_US
dc.subjectChemoradiotherapyen_US
dc.subjectChromosomesen_US
dc.subjectDNA Damageen_US
dc.subjectDNA Fragmentationen_US
dc.subjectDNA Repairen_US
dc.subjectFemaleen_US
dc.subjectHSP90 Heat-Shock Proteinsen_US
dc.subjectHead and Neck Neoplasmsen_US
dc.subjectHomologous Recombinationen_US
dc.subjectHumansen_US
dc.subjectIsoxazolesen_US
dc.subjectMice, Inbred BALB Cen_US
dc.subjectMice, Nudeen_US
dc.subjectOrganoplatinum Compoundsen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectResorcinolsen_US
dc.subjectSquamous Cell Carcinoma of Head and Necken_US
dc.subjectTumor Suppressor Protein p53en_US
dc.titleHSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-01-23en_US
rioxxterms.versionofrecord10.1186/s12885-017-3084-0en_US
rioxxterms.licenseref.startdate2017-01-31en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfBMC Canceren_US
pubs.issue1en_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.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished onlineen_US
pubs.volume17en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamTargeted Therapyen_US
dc.contributor.icrauthorMansfield, Daviden_US
dc.contributor.icrauthorHarrington, Kevinen_US
dc.contributor.icrauthorMcLaughlin, Martinen_US
dc.contributor.icrauthorDillon, Magnusen_US
dc.contributor.icrauthorKhan, Aadilen_US
dc.contributor.icrauthorMarsden,en_US


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