CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer
Abstract Poly (ADP‐ribose) Polymerase inhibitors (PARPi) have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to en...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202403782 |
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| author | Shini Liu Peng Deng Zhaoliang Yu Jing Han Hong Jiuping Gao Yulin Huang Rong Xiao Jiaxin Yin Xian Zeng Yichen Sun Peili Wang Ruizi Geng Jason Yongsheng Chan Peiyong Guan Qiang Yu Bin‐Tean Teh Qingping Jiang Xiaojun Xia Ying Xiong Jianfeng Chen Yongliang Huo Jing Tan |
| author_facet | Shini Liu Peng Deng Zhaoliang Yu Jing Han Hong Jiuping Gao Yulin Huang Rong Xiao Jiaxin Yin Xian Zeng Yichen Sun Peili Wang Ruizi Geng Jason Yongsheng Chan Peiyong Guan Qiang Yu Bin‐Tean Teh Qingping Jiang Xiaojun Xia Ying Xiong Jianfeng Chen Yongliang Huo Jing Tan |
| author_sort | Shini Liu |
| collection | DOAJ |
| description | Abstract Poly (ADP‐ribose) Polymerase inhibitors (PARPi) have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARPi, such as Olaparib. Here, compelling evidence indicates that sensitivity of PARPi is associated with cell cycle dysfunction. Through high‐throughput drug screening with a cell cycle kinase inhibitor library, XL413, a potent cell division cycle 7 (CDC7) inhibitor, is identified which can synergistically enhance the anti‐tumor efficacy of Olaparib. Mechanistically, the combined administration of XL413 and Olaparib demonstrates considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type‐I interferon response is triggered through the induction of the cGAS/STING signaling pathway. Using murine syngeneic tumor models, the combination treatment further demonstrates enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents an effective treatment strategy for patients with advanced OV by combining CDC7 inhibitors (CDC7i) and PARPi, offering a promising therapeutic approach for patients with limited response to PARPi. |
| format | Article |
| id | doaj-art-a6bbf8a7716f41d0811c53e342b2b0f7 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-a6bbf8a7716f41d0811c53e342b2b0f72025-08-20T02:19:01ZengWileyAdvanced Science2198-38442024-12-011145n/an/a10.1002/advs.202403782CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian CancerShini Liu0Peng Deng1Zhaoliang Yu2Jing Han Hong3Jiuping Gao4Yulin Huang5Rong Xiao6Jiaxin Yin7Xian Zeng8Yichen Sun9Peili Wang10Ruizi Geng11Jason Yongsheng Chan12Peiyong Guan13Qiang Yu14Bin‐Tean Teh15Qingping Jiang16Xiaojun Xia17Ying Xiong18Jianfeng Chen19Yongliang Huo20Jing Tan21State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong 510655 P. R. ChinaCancer and Stem Cell Biology Program Duke‐NUS Medical School Singapore 169857 SingaporeState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaDepartment of Laboratory Medicine Guangzhou First People's Hospital School of Medicine South China University of Technology Guangzhou 510180 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaExperimental Animal Center Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation School of Basic Medical Sciences Guangzhou Medical University Guangzhou 511436 P. R. ChinaDivision of Medical Sciences Laboratory of Cancer Epigenome National Cancer Centre Singapore Singapore 169610 SingaporeGenome Institute of Singapore A*STAR Singapore 138672 SingaporeCancer and Stem Cell Biology Program Duke‐NUS Medical School Singapore 169857 SingaporeCancer and Stem Cell Biology Program Duke‐NUS Medical School Singapore 169857 SingaporeDepartment of Patholgy Guangdong Provincial Key Laboratory of Major Obstetric Disease The Third Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510150 ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaExperimental Animal Center Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation School of Basic Medical Sciences Guangzhou Medical University Guangzhou 511436 P. R. ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaAbstract Poly (ADP‐ribose) Polymerase inhibitors (PARPi) have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARPi, such as Olaparib. Here, compelling evidence indicates that sensitivity of PARPi is associated with cell cycle dysfunction. Through high‐throughput drug screening with a cell cycle kinase inhibitor library, XL413, a potent cell division cycle 7 (CDC7) inhibitor, is identified which can synergistically enhance the anti‐tumor efficacy of Olaparib. Mechanistically, the combined administration of XL413 and Olaparib demonstrates considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type‐I interferon response is triggered through the induction of the cGAS/STING signaling pathway. Using murine syngeneic tumor models, the combination treatment further demonstrates enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents an effective treatment strategy for patients with advanced OV by combining CDC7 inhibitors (CDC7i) and PARPi, offering a promising therapeutic approach for patients with limited response to PARPi.https://doi.org/10.1002/advs.202403782CDC7 inhibitorimmune activationovarian cancerPARP inhibitor resistancetarget therapy |
| spellingShingle | Shini Liu Peng Deng Zhaoliang Yu Jing Han Hong Jiuping Gao Yulin Huang Rong Xiao Jiaxin Yin Xian Zeng Yichen Sun Peili Wang Ruizi Geng Jason Yongsheng Chan Peiyong Guan Qiang Yu Bin‐Tean Teh Qingping Jiang Xiaojun Xia Ying Xiong Jianfeng Chen Yongliang Huo Jing Tan CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer Advanced Science CDC7 inhibitor immune activation ovarian cancer PARP inhibitor resistance target therapy |
| title | CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer |
| title_full | CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer |
| title_fullStr | CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer |
| title_full_unstemmed | CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer |
| title_short | CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer |
| title_sort | cdc7 inhibition potentiates antitumor efficacy of parp inhibitor in advanced ovarian cancer |
| topic | CDC7 inhibitor immune activation ovarian cancer PARP inhibitor resistance target therapy |
| url | https://doi.org/10.1002/advs.202403782 |
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