Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer

// Paul M Wilkerson 1, * , Konstantin J Dedes 1, 2, * , Eleftherios Pierre Samartzis 2 , Ioannis Dedes 2 , Maryou B Lambros 1 , Rachael Natrajan 1 , Arnaud Gauthier 1 , Salvatore Piscuoglio 3 , Chantal Topfer 1 , Vesna Vukovic 1 , Frances Daley 1 , Britta Weigelt 3 , Jorge S Reis-Filho 1, 3 1 The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK 2 Department of Gynaecology, University Hospital of Zurich, 8091 Zurich, CH 3 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA * These authors contributed equally to this work Correspondence to: Jorge S Reis-Filho, email: reisfilj@mskcc.org Konstantin J Dedes, email: konstantin.dedes@usz.ch Keywords: ovarian clear cell carcinoma, homologous recombination, PTEN, PARP inhibitors Received: July 24, 2015      Accepted: December 10, 2016      Published: December 17, 2016 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.