dc.contributor.author | McLaughlin, M | |
dc.contributor.author | Barker, HE | |
dc.contributor.author | Khan, AA | |
dc.contributor.author | Pedersen, M | |
dc.contributor.author | Dillon, M | |
dc.contributor.author | Mansfield, DC | |
dc.contributor.author | Patel, R | |
dc.contributor.author | Kyula, JN | |
dc.contributor.author | Bhide, SA | |
dc.contributor.author | Newbold, KL | |
dc.contributor.author | Nutting, CM | |
dc.contributor.author | Harrington, KJ | |
dc.date.accessioned | 2017-02-28T11:58:20Z | |
dc.date.issued | 2017-01-31 | |
dc.identifier.citation | BMC cancer, 2017, 17 (1), pp. 86 - ? | |
dc.identifier.issn | 1471-2407 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/409 | |
dc.identifier.eissn | 1471-2407 | |
dc.identifier.doi | 10.1186/s12885-017-3084-0 | |
dc.description.abstract | BACKGROUND: 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. | |
dc.format | Electronic | |
dc.format.extent | 86 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | BIOMED CENTRAL LTD | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Chromosomes | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Humans | |
dc.subject | Mice, Nude | |
dc.subject | Carcinoma, Squamous Cell | |
dc.subject | Head and Neck Neoplasms | |
dc.subject | DNA Damage | |
dc.subject | Organoplatinum Compounds | |
dc.subject | Resorcinols | |
dc.subject | Isoxazoles | |
dc.subject | BRCA1 Protein | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | DNA Fragmentation | |
dc.subject | DNA Repair | |
dc.subject | Female | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.subject | HSP90 Heat-Shock Proteins | |
dc.subject | Chemoradiotherapy | |
dc.subject | Homologous Recombination | |
dc.subject | Squamous Cell Carcinoma of Head and Neck | |
dc.title | HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-01-23 | |
rioxxterms.versionofrecord | 10.1186/s12885-017-3084-0 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-01-31 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | BMC cancer | |
pubs.issue | 1 | |
pubs.notes | No embargo | |
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.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-status | Published | |
pubs.volume | 17 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Targeted Therapy | |
dc.contributor.icrauthor | McLaughlin, Martin | |
dc.contributor.icrauthor | Dillon, Magnus | |
dc.contributor.icrauthor | Mansfield, David | |
dc.contributor.icrauthor | Bhide, Shreerang | |
dc.contributor.icrauthor | Harrington, Kevin | |