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Mol Cancer Res. 2014 Mar;12(3):381-393. doi: 10.1158/1541-7786.MCR-13-0480. Epub 2014 Jan 10.

Triapine disrupts CtIP-mediated homologous recombination repair and sensitizes ovarian cancer cells to PARP and topoisomerase inhibitors.

Author information

1
Department of Pharmacology, Yale Cancer Center,Yale University School of Medicine, New Haven, Connecticut.
2
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Yale Cancer Center,Yale University School of Medicine, New Haven, Connecticut.
3
Department of Internal Medicine, Section of Nephrology, Yale Cancer Center,Yale University School of Medicine, New Haven, Connecticut.
#
Contributed equally

Abstract

PARP inhibitors exploit synthetic lethality to target epithelial ovarian cancer (EOC) with hereditary BRCA mutations and defects in homologous recombination repair (HRR). However, such an approach is limited to a small subset of EOC patients and compromised by restored HRR due to secondary mutations in BRCA genes. Here, it was demonstrated that triapine, a small-molecule inhibitor of ribonucleotide reductase, enhances the sensitivity of BRCA wild-type EOC cells to the PARP inhibitor olaparib and the topoisomerase II inhibitor etoposide. Triapine abolishes olaparib-induced BRCA1 and Rad51 foci, and disrupts the BRCA1 interaction with the Mre11-Rad50-Nbs1 (MRN) complex in BRCA1 wild-type EOC cells. It has been shown that phosphorylation of CtIP (RBBP8) is required for the interaction with BRCA1 and with MRN to promote DNA double-strand break (DSB) resection during S and G(2) phases of the cell cycle. Mechanistic studies within reveal that triapine inhibits cyclin-dependent kinase (CDK) activity and blocks olaparib-induced CtIP phosphorylation through Chk1 activation. Furthermore, triapine abrogates etoposide-induced CtIP phosphorylation and DSB resection as evidenced by marked attenuation of RPA32 phosphorylation. Concurrently, triapine obliterates etoposide-induced BRCA1 foci and sensitizes BRCA1 wild-type EOC cells to etoposide. Using a GFP-based HRR assay, it was determined that triapine suppresses HRR activity induced by an I-SceI-generated DSB. These results suggest that triapine augments the sensitivity of BRCA wild-type EOC cells to drug-induced DSBs by disrupting CtIP-mediated HRR.

IMPLICATIONS:

These findings provide a strong rationale for combining triapine with PARP or topoisomerase inhibitors to target HRR-proficient EOC cells.

PMID:
24413181
PMCID:
PMC3962722
DOI:
10.1158/1541-7786.MCR-13-0480
[Indexed for MEDLINE]
Free PMC Article

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