dc.contributor.author | Jones, SE | |
dc.contributor.author | Fleuren, EDG | |
dc.contributor.author | Frankum, J | |
dc.contributor.author | Konde, A | |
dc.contributor.author | Williamson, CT | |
dc.contributor.author | Krastev, DB | |
dc.contributor.author | Pemberton, HN | |
dc.contributor.author | Campbell, J | |
dc.contributor.author | Gulati, A | |
dc.contributor.author | Elliott, R | |
dc.contributor.author | Menon, M | |
dc.contributor.author | Selfe, JL | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Niedzwiedz, W | |
dc.contributor.author | van der Graaf, WTA | |
dc.contributor.author | Shipley, J | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Lord, CJ | |
dc.date.accessioned | 2017-09-29T10:53:29Z | |
dc.date.issued | 2017-12-15 | |
dc.identifier.citation | Cancer research, 2017, 77 (24), pp. 7014 - 7026 | |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/844 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.doi | 10.1158/0008-5472.can-17-2056 | |
dc.description.abstract | Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells with those in >130 non-SS tumor cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18-SSX family fusion genes are known to alter the composition of the BAF chromatin-remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18-SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18-SSX1 Δ71-78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the antitumor cell effect of ATRi, suggesting that either single-agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment. Cancer Res; 77(24); 7014-26. ©2017 AACR. | |
dc.format | Print-Electronic | |
dc.format.extent | 7014 - 7026 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Tumor Cells, Cultured | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Mice, Inbred NOD | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Mice, SCID | |
dc.subject | Sarcoma, Synovial | |
dc.subject | Recombinant Fusion Proteins | |
dc.subject | RNA, Small Interfering | |
dc.subject | Antineoplastic Agents | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Cell Death | |
dc.subject | Cell Proliferation | |
dc.subject | RNA Interference | |
dc.subject | Female | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | Ataxia Telangiectasia Mutated Proteins | |
dc.title | ATR Is a Therapeutic Target in Synovial Sarcoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-10-10 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1158/0008-5472.can-17-2056 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2017-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer research | |
pubs.issue | 24 | |
pubs.notes | Not known | |
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/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Cancer and Genome Instability | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical and Translational Sarcoma | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology | |
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/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Cancer and Genome Instability | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical and Translational Sarcoma | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology | |
pubs.publication-status | Published | |
pubs.volume | 77 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer and Genome Instability | |
icr.researchteam | Clinical and Translational Sarcoma | |
icr.researchteam | Gene Function | |
icr.researchteam | Sarcoma Molecular Pathology | |
dc.contributor.icrauthor | Jones, Samuel | |
dc.contributor.icrauthor | Krastev, Dragomir | |
dc.contributor.icrauthor | Campbell, James | |
dc.contributor.icrauthor | Selfe, Joanna | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Niedzwiedz, Wojciech | |
dc.contributor.icrauthor | Shipley, Janet | |
dc.contributor.icrauthor | Lord, Christopher | |