CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer

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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Main Authors: 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
Format: Article
Language:English
Published: Wiley 2024-12-01
Series:Advanced Science
Subjects:
CDC7 inhibitor
immune activation
ovarian cancer
PARP inhibitor resistance
target therapy
Online Access:https://doi.org/10.1002/advs.202403782
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Summary: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.
ISSN:2198-3844

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