title: Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wilkerson
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.|Department of Gynaecology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Konstantin J
authors.initials: KJ
authors.lastname: Dedes
authors.affiliation: Department of Gynaecology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Eleftherios Pierre
authors.initials: EP
authors.lastname: Samartzis
authors.affiliation: Department of Gynaecology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dedes
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Maryou B
authors.initials: MB
authors.lastname: Lambros
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gauthier
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Chantal
authors.initials: C
authors.lastname: Töpfer
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Vesna
authors.initials: V
authors.lastname: Vukovic
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Daley
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D000076228:MRE11 Homologue Protein / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D046888:Tissue Array Analysis
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C121766:MRE11 protein, human; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C586365:talazoparib; D000076228:MRE11 Homologue Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D002945:Cisplatin
keywords: PARP inhibitors; PTEN; homologous recombination; ovarian clear cell carcinoma