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

Paul M Wilkerson,Maryou B Lambros,Jorge S Reis-Filho,Frances Daley,Eleftherios Pierre Samartzis,Arnaud Gauthier,Chantal Töpfer,Britta Weigelt,Rachael Natrajan,Salvatore Piscuoglio,Vesna Vukovic,Konstantin J Dedes,Ioannis Dedes

doi:10.18632/oncotarget.14011

Abstract

PurposeTo 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 DesignThe 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.ResultsA 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.ConclusionsA 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.

Highlights

Ovarian clear cell carcinoma (OCCC) is an aggressive histological subtype of epithelial ovarian cancer (EOC) with a higher rate of de novo resistance to platinumbased chemotherapy than high-grade serous EOCs [1, 2]
In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases
A subset of OCCC cells are sensitive to Poly(ADP) ribose polymerase (PARP) inhibition in vitro, which can be predicted by homologous recombination (HR) defects as defined by γH2AX/RAD51 foci formation

Summary

Introduction

Ovarian clear cell carcinoma (OCCC) is an aggressive histological subtype of epithelial ovarian cancer (EOC) with a higher rate of de novo resistance to platinumbased chemotherapy than high-grade serous EOCs [1, 2]. OCCCs are characterised by the presence of ARID1A mutations [5], activating PIK3CA mutations [6], loss of PTEN expression [6, 7], and amplification of PPM1D [8] It should be noted, that there is evidence to suggest that OCCCs constitute a heterogeneous group of cancers at the genetic level, exemplified by the existence of subgroups harbouring distinct constellations of gene copy number alterations [9] and a varied repertoire of somatic mutations [5]. That the heterogeneity of OCCCs is apparent in terms of its response to specific therapeutic agents, as there are models of OCCCs that have been shown to be sensitive to platinum salts [2]

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Conclusion