dc.contributor.author | Wilkerson, PM | |
dc.contributor.author | Dedes, KJ | |
dc.contributor.author | Samartzis, EP | |
dc.contributor.author | Dedes, I | |
dc.contributor.author | Lambros, MB | |
dc.contributor.author | Natrajan, R | |
dc.contributor.author | Gauthier, A | |
dc.contributor.author | Piscuoglio, S | |
dc.contributor.author | Töpfer, C | |
dc.contributor.author | Vukovic, V | |
dc.contributor.author | Daley, F | |
dc.contributor.author | Weigelt, B | |
dc.contributor.author | Reis-Filho, JS | |
dc.date.accessioned | 2018-06-15T12:59:19Z | |
dc.date.issued | 2017-01-24 | |
dc.identifier.citation | Oncotarget, 2017, 8 (4), pp. 6057 - 6066 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/1889 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.14011 | |
dc.description.abstract | PURPOSE: 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.format | Print | |
dc.format.extent | 6057 - 6066 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Ovarian Neoplasms | |
dc.subject | Cisplatin | |
dc.subject | Phthalazines | |
dc.subject | BRCA1 Protein | |
dc.subject | BRCA2 Protein | |
dc.subject | Tissue Array Analysis | |
dc.subject | Drug Screening Assays, Antitumor | |
dc.subject | DNA Repair | |
dc.subject | Female | |
dc.subject | PTEN Phosphohydrolase | |
dc.subject | DNA Breaks, Double-Stranded | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | MRE11 Homologue Protein | |
dc.title | Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-12-10 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.14011 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 4 | |
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/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-status | Published | |
pubs.volume | 8 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Functional Genomics | |
dc.contributor.icrauthor | Natrajan, Rachael | |