Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer Journal Article
| Authors: | Wilkerson, P. M.; Dedes, K. J.; Samartzis, E. P.; Dedes, I.; Lambros, M. B.; Natrajan, R.; Gauthier, A.; Piscuoglio, S.; Töpfer, C.; Vukovic, V.; Daley, F.; Weigelt, B.; Reis-Filho, J. S. |
| Article Title: | Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer |
| 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. |
| Keywords: | homologous recombination; pten; ovarian clear cell carcinoma; parp inhibitors |
| Journal Title: | Oncotarget |
| Volume: | 8 |
| Issue: | 4 |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Date Published: | 2017-01-01 |
| Start Page: | 6057 |
| End Page: | 6066 |
| Language: | English |
| DOI: | 10.18632/oncotarget.14011 |
| PROVIDER: | scopus |
| PUBMED: | 28002809 |
| PMCID: | PMC5351612 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 March 2017 -- Source: Scopus |
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