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dc.contributor.authorJones, SEen_US
dc.contributor.authorFleuren, EDGen_US
dc.contributor.authorFrankum, Jen_US
dc.contributor.authorKonde, Aen_US
dc.contributor.authorWilliamson, CTen_US
dc.contributor.authorKrastev, DBen_US
dc.contributor.authorPemberton, HNen_US
dc.contributor.authorCampbell, Jen_US
dc.contributor.authorGulati, Aen_US
dc.contributor.authorElliott, Ren_US
dc.contributor.authorMenon, Men_US
dc.contributor.authorSelfe, JLen_US
dc.contributor.authorBrough, Ren_US
dc.contributor.authorPettitt, SJen_US
dc.contributor.authorNiedzwiedz, Wen_US
dc.contributor.authorvan der Graaf, WTAen_US
dc.contributor.authorShipley, Jen_US
dc.contributor.authorAshworth, Aen_US
dc.contributor.authorLord, CJen_US
dc.date.accessioned2017-09-29T10:53:29Z
dc.date.issued2017-12en_US
dc.identifier.citationCancer research, 2017, 77 (24), pp. 7014 - 7026en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/844
dc.identifier.eissn1538-7445en_US
dc.identifier.doi10.1158/0008-5472.can-17-2056en_US
dc.description.abstractSynovial 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.en_US
dc.formatPrint-Electronicen_US
dc.format.extent7014 - 7026en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectTumor Cells, Cultureden_US
dc.subjectAnimalsen_US
dc.subjectMice, Inbred BALB Cen_US
dc.subjectMice, Inbred NODen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectMice, Nudeen_US
dc.subjectMice, SCIDen_US
dc.subjectSarcoma, Synovialen_US
dc.subjectRecombinant Fusion Proteinsen_US
dc.subjectRNA, Small Interferingen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.subjectCell Deathen_US
dc.subjectCell Proliferationen_US
dc.subjectRNA Interferenceen_US
dc.subjectFemaleen_US
dc.subjectMolecular Targeted Therapyen_US
dc.subjectAtaxia Telangiectasia Mutated Proteinsen_US
dc.titleATR Is a Therapeutic Target in Synovial Sarcoma.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-10-10en_US
rioxxterms.funderThe Institute of Cancer Researchen_US
rioxxterms.identifier.projectUnspecifieden_US
rioxxterms.versionofrecord10.1158/0008-5472.can-17-2056en_US
rioxxterms.licenseref.startdate2017-12en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfCancer researchen_US
pubs.issue24en_US
pubs.notesNot knownen_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/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-statusPublisheden_US
pubs.volume77en_US
pubs.embargo.termsNot knownen_US
icr.researchteamCancer and Genome Instabilityen_US
icr.researchteamClinical and Translational Sarcomaen_US
icr.researchteamGene Functionen_US
icr.researchteamSarcoma Molecular Pathologyen_US
dc.contributor.icrauthorvan der Graaf, Wilhelminaen_US
dc.contributor.icrauthorLord, Christopheren_US
dc.contributor.icrauthorSelfe, Joannaen_US
dc.contributor.icrauthorNiedzwiedz, Wojciechen_US
dc.contributor.icrauthorShipley, Janeten_US
dc.contributor.icrauthorCampbell, Jamesen_US
dc.contributor.icrauthorKrastev, Dragomiren_US
dc.contributor.icrauthorJones, Samuelen_US
dc.contributor.icrauthorPettitt, Stephenen_US
rioxxterms.funder.project354849bd-c553-4e22-868c-8c503e124155en_US


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