- Gynecologic Cancer
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Enhanced Efficacy of Combined Therapy with Checkpoint Kinase 1 Inhibitor and Rucaparib via Regulation of Rad51 Expression in BRCA Wild-Type Epithelial Ovarian Cancer Cells
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Hye-yon Cho, Yong-Beom Kim, Wook-ha Park, Jae Hong No
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Cancer Res Treat. 2021;53(3):819-828. Published online December 16, 2020
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DOI: https://doi.org/10.4143/crt.2020.1013
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 Abstract
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- Purpose
This study aimed to evaluate anticancer effects of combination treatment with poly(ADP-ribose) polymerase (PARP) and checkpoint kinase 1 (Chk1) inhibitors in BRCA wild-type ovarian cancer. PARP inhibitors can function as DNA-damaging agents in BRCA wild-type cancer, even if clinical activity is limited. Most epithelial ovarian cancers are characterized by a TP53 mutation causing dysfunction at the G1/S checkpoint, which makes tumor cells highly dependent on Chk1-mediated G/M phase cell-cycle arrest for DNA repair.
Materials and Methods
We investigated the anticancer effects of combination treatment with prexasertib (LY2606368), a selective ATP competitive small molecule inhibitor of Chk1 and Chk2, and rucaparib, a PARP inhibitor, in BRCA wild-type ovarian cancer cell lines (OVCAR3 and SKOV3).
Results
We found that combined treatment significantly decreased cell viability in all cell lines and induced greater DNA damage and apoptosis than in the control and/or using monotherapies. Moreover, we found that prexasertib significantly inhibited homologous recombination–mediated DNA repair and thus showed a marked anticancer effect in combination treatment with rucaparib. The anticancer mechanism of prexasertib and rucaparib was considered to be caused by an impaired G2/M checkpoint due to prexasertib treatment, which forced mitotic catastrophe in the presence of rucaparib.
Conclusion
Our results suggest a novel effective therapeutic strategy for BRCA wild-type epithelial ovarian cancer using a combination of Chk1 and PARP inhibitors.
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Citations
Citations to this article as recorded by  - ATR, CHK1 and WEE1 inhibitors cause homologous recombination repair deficiency to induce synthetic lethality with PARP inhibitors
Hannah L. Smith, Elaine Willmore, Lisa Prendergast, Nicola J. Curtin
British Journal of Cancer.2024; 131(5): 905. CrossRef - Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer
Yijun Xie, Di Xiao, Duo Li, Mei Peng, Wei Peng, Huaxin Duan, Xiaoping Yang
Frontiers in Oncology.2024;[Epub] CrossRef - Update on Combination Strategies of PARP Inhibitors
Zhuoqun Lin, Lingfang Wang, Ziyu Xing, Fenfen Wang, Xiaodong Cheng
Cancer Control.2024;[Epub] CrossRef - Molecular Methods for Increasing the Effectiveness of Ovarian Cancer Treatment: A Systematic Review
Zuzanna Chilimoniuk, Agata Rocka, Martyna Stefaniak, Żaklina Tomczyk, Faustyna Jasielska, Dominika Madras, Agata Filip
Future Oncology.2022; 18(13): 1627. CrossRef - A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer
Panagiotis A. Konstantinopoulos, Jung-min Lee, Bo Gao, Rowan Miller, Jung-Yun Lee, Nicoletta Colombo, Ignace Vergote, Kelly M. Credille, Suzanne R. Young, Samuel McNeely, Xuejing Aimee Wang, Aimee Bence Lin, Ronnie Shapira-Frommer
Gynecologic Oncology.2022; 167(2): 213. CrossRef - Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages
Cassandra L. R. van Doorn, Sanne A. M. Steenbergen, Kimberley V. Walburg, Tom H. M. Ottenhoff
Frontiers in Immunology.2021;[Epub] CrossRef
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