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

Fragestellung:

Ovarian clear cell carcinoma (OCCC) is an aggressive histological subtype of epithelial ovarian cancer. De-novo resistance to platinum-based chemotherapy is higher compared to serous ovarian cancers. The aims of this study were to examine the role of a potent poly(ADP) ribose polymerase (PARP)-inhibitor as a potential therapeutic option for OCCCs and if RAD51 foci formation would constitute a surrogate marker for the use of these agents in OCCCs.

Methode:

Twelve OCCC cell lines were tested for their ability to elicit phospho-γ-H2AX foci (a marker of induction of DNA damage) and RAD51 foci (a marker of competent homologous recombination (HR) DNA repair) when challenged with ionising radiation. The sensitivity of these cell lines to the PARP inhibitor olaparib and to cisplatin was tested in vitro.

Ergebnisse:

Out of the 12 OCCC cell lines tested, 5 (TOV-21, KK, SMOV-2, RMG-I, KOC-7) were unable to elicit RAD51 foci formation. Of these cell lines, all but one (i.e. KOC7) were sensitive to cisplatin and olaparib and cisplatin. Multidrug resistance 1 (MDR1) protein was expressed in KOC7 and combination treatment with olaparib and verapamil increased sensitivity to olaparib.

Schlussfolgerung:

A subset of OCCC exhibits impaired HR DNA repair and may therefore respond to PARP-inhibition. RAD51 foci formation and sensitivity to platinum salts are predictive for sensitivity to olaparib. Overexpression of MDR1 may constitute a mechanism of resistance to olaparib in OCCCs.