CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer
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.
Authors
- Xiaojun Xia (ORCID: https://orcid.org/0000-0003-4444-7472)
- Jing Han Hong (ORCID: https://orcid.org/0000-0002-2173-9192)
- Jing Ying Tan (ORCID: https://orcid.org/0000-0002-4605-4624)
- Shini Liu
- Bin Tean Teh (ORCID: https://orcid.org/0000-0003-1514-1124)
- Jason Yongsheng Chan (ORCID: https://orcid.org/0000-0002-4801-3703)
- Ruixuan Geng (ORCID: https://orcid.org/0000-0002-3523-9367)
- Xian Zeng (ORCID: https://orcid.org/0000-0001-5875-3599)
- Rong Xiao (ORCID: https://orcid.org/0000-0002-6214-8057)
- Yi-Chen Sun (ORCID: https://orcid.org/0000-0002-3247-0774)
- Peiyong Guan (ORCID: https://orcid.org/0000-0001-9958-0137)
- Zhaoliang Yu (ORCID: https://orcid.org/0000-0003-2964-9834)
- Jianfeng Chen (ORCID: https://orcid.org/0000-0002-4182-145X)
- Peng Deng (ORCID: https://orcid.org/0000-0001-5781-090X)
- Qiang Yu (ORCID: https://orcid.org/0000-0003-2132-8278)
- Jiaxin Yin
- Yulin Huang (ORCID: https://orcid.org/0000-0002-0997-7200)
- Qingping Jiang (ORCID: https://orcid.org/0000-0001-9572-2708)
- Peili Wang (ORCID: https://orcid.org/0000-0003-4838-5723)
- Jiuping Gao (ORCID: https://orcid.org/0009-0007-0511-8867)
- Ying Xiong (ORCID: https://orcid.org/0009-0000-1747-2416)
- Yongliang Huo (ORCID: https://orcid.org/0000-0003-3880-8622)
Institutions
- Agency for Science, Technology and Research (SG)
- Sun Yat-sen University (CN)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Sun Yat-sen Memorial Hospital (CN)
- Guangzhou First People's Hospital (CN)
- Duke-NUS Medical School (SG)
- National Cancer Centre Singapore (SG)
- Guangdong Academy of Medical Sciences (CN)
- Sun Yat-sen University Cancer Center (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
- Genome Institute of Singapore (SG)
- Hainan Medical University (CN)
- South China University of Technology (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1002/advs.202403782
- Citations
- 10
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 2.83
Funders
- Guangdong Innovative and Entrepreneurial Research Team Program
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- National Key Research and Development Program of China