Targeting CLK1/SRSF7 axis-dependent alternative splicing sensitizes pancreatic ductal adenocarcinoma to chemotherapy and immunotherapy

作者：Chun Zhang, Yinhao Chen, Shun‐Cang Zhu, Zuwei Wang, Hongyi Lin, Jinpeng Lu, Haoxiang Zhang, Yueyi Weng, Xiaoxiao Huang, Ge Li, Yongding Wu, Zhiyuan Li, Jianfei Hu, Chengke Xie, Jianlin Lai, Yi-Feng Tian, Cheng‐Yu Liao, Shi Chen · 发表于：Drug Resistance Updates · 年份：2025 · DOI：10.1016/j.drup.2025.101292 · 被引用次数：10 · 研究领域：Circular RNAs in diseases、Cancer-related molecular mechanisms research、Cancer Mechanisms and Therapy

AIM: The persistently high mortality rate of pancreatic ductal adenocarcinoma (PDAC) is largely attributed to the acquired resistance to chemotherapy, particularly gemcitabine. This study aims to elucidate the underlying molecular mechanisms of gemcitabine resistance in PDAC, uncover additional pro-tumorigenic factors contributing to drug resistance, and develop more effective and safer targeted therapeutic strategies against this phenomenon. METHODS: Circular RNA (circRNA) sequencing was employed to identify differentially expressed circRNAs between chemo-sensitive and resistant tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) was utilized to uncover the RNA-binding proteins (RBPs) associated with circular RNA of alpha-1, 3-glucosyltransferase 8 (cALG8). Molecular biology techniques were applied to explore the biological functions and regulatory mechanisms of cALG8 in the context of gemcitabine resistance in PDAC. Single-cell sequencing was performed to reveal changes in the composition of tumor immune microenvironment of pancreatic cancer. Patient-Derived Organoid (PDO) and Patient-Derived Xenograft (PDX) were employed to further validate the molecular mechanisms. Finally, antisense oligonucleotides (ASOs) targeting cALG8 were developed for in vivo use, and their translational therapeutic potential was evaluated in mouse models. RESULTS: This study identified that cALG8, which is associated with alternative splicing, is highly expressed in gemcitabine-resistant PDAC ...