Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer.
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Date
2017-01-24ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Humans
Ovarian Neoplasms
Cisplatin
Phthalazines
BRCA1 Protein
BRCA2 Protein
Tissue Array Analysis
Drug Screening Assays, Antitumor
DNA Repair
Female
PTEN Phosphohydrolase
DNA Breaks, Double-Stranded
Poly(ADP-ribose) Polymerase Inhibitors
MRE11 Homologue Protein
Research team
Functional Genomics
Language
eng
Date accepted
2016-12-10
License start date
2017-01
Citation
Oncotarget, 2017, 8 (4), pp. 6057 - 6066
Publisher
IMPACT JOURNALS LLC