PARP inhibitor augments anti-tumor efficacy of DNMT inhibitor by inducing senescence in cholangiocarcinoma

作者：Peili Wang, Rong Xiao, Jianfeng Chen, Peiyong Guan, Hong Lee Heng, Lizhen Liu, Yali Wang, Xian Zeng, Guixiang Zhong, Jing Hao, Jiuping Gao, Jason Yongsheng Chan, Simona Dima, Choon Kiat Ong, Bin Tean Teh, Mei Li, Jing Han Hong, Jing Tan · 发表于：International Journal of Biological Sciences · 年份：2025 · DOI：10.7150/ijbs.110947 · 被引用次数：8 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、PARP inhibition in cancer therapy、Drug Transport and Resistance Mechanisms

Cholangiocarcinoma (CCA) is an aggressive, heterogeneous malignancy with limited effective treatment options.One of the key epigenetic dysregulations in CCA is aberrant DNA hypermethylation, suggesting that targeted DNA methylation is a promising therapeutic strategy for this disease.However, there is still limited information on how effective DNA demethylating agents are in the treatment of CCA in the clinical setting, and further studies are urgently needed to evaluate their potential benefits.Here, we established four patient-derived CCA cell lines and demonstrated that the DNA methyltransferase (DMNT) inhibitors decitabine and azacitidine had minimal effects on inhibiting CCA proliferation.A combinatorial drug screen identified PARP inhibitors as sensitizers that synergistically enhanced the antitumor effects of decitabine.The combination of DNMT inhibitors and PARP inhibitors therapeutically inhibited the growth of CCA cancers in multiple in vitro cancer cell lines and organoid models, as well as in vivo cell line-derived xenografts, patient-derived xenograft models, and CCA in mice induced by hydrodynamic tail vein injection.Mechanistically, transcriptomic profiling analysis showed that combination treatment activated the inflammatory signaling pathway and suppressed the cell cycle-related pathways in CCA.In addition, the combination synergistically induced DNA damage and cellular senescence of CCA cancer cells.Together, our study provides a preclinical proof-of-concept...