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

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

Oncotarget. 2016 Dec 17;:

Authors: Wilkerson PM, Dedes KJ, Samartzis EP, Dedes I, Lambros MB, Natrajan R, Gauthier A, Piscuoglio S, Töpfer C, Vukovic V, Daley F, Weigelt B, Reis-Filho JS

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.

PMID: 28002809 [PubMed - as supplied by publisher]

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