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Int J Clin Oncol. 2017 Aug;22(4):619-628. doi: 10.1007/s10147-017-1145-7. Epub 2017 Jun 22.

Targeting DNA repair and replication stress in the treatment of ovarian cancer.

Author information

1
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. junko.murai@nih.gov.

Abstract

Approximately half of high-grade serous epithelial ovarian cancers incur alterations in genes of homologous recombination (BRCA1, BRCA2, RAD51C, Fanconi anemia genes), and the rest incur alterations in other DNA repair pathways at high frequencies. Such cancer-specific gene alterations can confer selective sensitivity to DNA damaging agents such as cisplatin and carboplatin, topotecan, etoposide, doxorubicin, and gemcitabine. Originally presumed to inhibit DNA repair, PARP inhibitors that have recently been approved by the FDA for the treatment of advanced ovarian cancer also act as DNA damaging agents by inducing PARP-DNA complexes. These DNA damaging agents induce different types of DNA lesions that require various DNA repair genes for the repair, but commonly induce replication fork slowing or stalling, also referred to as replication stress. Replication stress activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further DNA damage. Hence, targeting DNA repair genes or DNA repair checkpoint genes augments the anti-tumor activity of DNA damaging agents. This review describes the rational basis for using DNA repair and DNA repair checkpoint inhibitors as single agents. The review also presents the strategies combining these inhibitors with DNA damaging agents for ovarian cancer therapy based on specific gene alterations.

KEYWORDS:

ATR; BRCA; CHK1; Cell cycle; Cell cycle checkpoint inhibitor; Cisplatin; DNA damage; Homologous recombination; PARP inhibitor; Replication stress; Synthetic lethality; Topoisomerase inhibitor

PMID:
28643177
DOI:
10.1007/s10147-017-1145-7
[Indexed for MEDLINE]

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