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

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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.

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Acknowledgements

I am grateful to Drs. Jung-Min Lee (Women’s Malignancies Branch, CCR, NCI, NIH) and Shar-Yin N Huang (Developmental Therapeutics Branch, CCR, NCI, NIH) for careful and professional review of this manuscript.

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  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

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  1. Junko Murai
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Correspondence to Junko Murai.

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Junko Murai has no conflict of interest to disclose.

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Murai, J. Targeting DNA repair and replication stress in the treatment of ovarian cancer. Int J Clin Oncol 22, 619–628 (2017). https://doi.org/10.1007/s10147-017-1145-7

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  • DOI: https://doi.org/10.1007/s10147-017-1145-7

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