Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer
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Paul M Wilkerson1,*, Konstantin J Dedes1,2,*, Eleftherios Pierre Samartzis2, Ioannis Dedes2, Maryou B Lambros1, Rachael Natrajan1, Arnaud Gauthier1, Salvatore Piscuoglio3, Chantal Töpfer1, Vesna Vukovic1, Frances Daley1, Britta Weigelt3, Jorge S Reis-Filho1,3
1The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
2Department of Gynaecology, University Hospital of Zurich, 8091 Zurich, CH
3Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
*These authors contributed equally to this work
Jorge S Reis-Filho, email: firstname.lastname@example.org
Konstantin J Dedes, email: email@example.com
Keywords: ovarian clear cell carcinoma, homologous recombination, PTEN, PARP inhibitors
Received: July 24, 2015 Accepted: December 10, 2016 Published: December 17, 2016
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.
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