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Advanced Science

Advanced Science

IF: 14.3
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CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer

Published:16 October 2024 DOI: PMID: 39412086
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

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.

Substances (16)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Niraparib 1038915-60-4 C19H20N4O 329 suppliers Inquiry
Niraparib 1038915-60-4 C19H20N4O 329 suppliers Inquiry
Niraparib 1038915-60-4 C19H20N4O 329 suppliers Inquiry
Niraparib 1038915-60-4 C19H20N4O 329 suppliers Inquiry
BMN 673 1207456-01-6 C19H14F2N6O 219 suppliers $18.00-$2839.00
BMN 673 1207456-01-6 C19H14F2N6O 219 suppliers $18.00-$2839.00
BMN 673 1207456-01-6 C19H14F2N6O 219 suppliers $18.00-$2839.00
BMN 673 1207456-01-6 C19H14F2N6O 219 suppliers $18.00-$2839.00
PHA 767491 HYDROCHLORIDE 845714-00-3 C12H11N3O 117 suppliers $35.00-$2260.00
PHA 767491 HYDROCHLORIDE 845714-00-3 C12H11N3O 117 suppliers $35.00-$2260.00

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