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dc.contributor.authorWilkerson, PM
dc.contributor.authorDedes, KJ
dc.contributor.authorSamartzis, EP
dc.contributor.authorDedes, I
dc.contributor.authorLambros, MB
dc.contributor.authorNatrajan, R
dc.contributor.authorGauthier, A
dc.contributor.authorPiscuoglio, S
dc.contributor.authorTöpfer, C
dc.contributor.authorVukovic, V
dc.contributor.authorDaley, F
dc.contributor.authorWeigelt, B
dc.contributor.authorReis-Filho, JS
dc.date.accessioned2018-06-15T12:59:19Z
dc.date.issued2017-01
dc.identifier.citationOncotarget, 2017, 8 (4), pp. 6057 - 6066
dc.identifier.issn1949-2553
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1889
dc.identifier.eissn1949-2553
dc.identifier.doi10.18632/oncotarget.14011
dc.description.abstractPurpose To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition.Experimental design The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry.Results A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 -9.4 (SD +/- 0.29) vs -8.1 (SD +/- 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases.Conclusions A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by γH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs.
dc.formatPrint
dc.format.extent6057 - 6066
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectOvarian Neoplasms
dc.subjectCisplatin
dc.subjectPhthalazines
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectTissue Array Analysis
dc.subjectDrug Screening Assays, Antitumor
dc.subjectDNA Repair
dc.subjectFemale
dc.subjectPTEN Phosphohydrolase
dc.subjectDNA Breaks, Double-Stranded
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectMRE11 Homologue Protein
dc.titlePreclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer.
dc.typeJournal Article
dcterms.dateAccepted2016-12-10
rioxxterms.versionofrecord10.18632/oncotarget.14011
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncotarget
pubs.issue4
pubs.notesNot 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/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
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/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.publication-statusPublished
pubs.volume8
pubs.embargo.termsNot known
icr.researchteamFunctional Genomicsen_US
dc.contributor.icrauthorNatrajan, Rachaelen


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