Background Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified. Objective We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA. Design We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)—an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors—in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms. Results PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions. Conclusion PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies. Data are available on reasonable request.

中文翻译：

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确定 PRMT5 作为胆管癌的治疗靶点


背景 胆管癌 （CCA） 是一种非常难以治疗的癌症。化疗效果不佳，对免疫检查点抑制剂的反应有限。因此，需要确定新的治疗策略。目的 我们将酶蛋白精氨酸-甲基转移酶 5 （PRMT5） 表征为 CCA 的新型治疗靶点。设计我们评估了 PRMT5、其功能伴侣 MEP50 和甲硫代腺苷磷酸化酶 （MTAP） 的表达——一种调节 PRMT5 对药物抑制剂敏感性的酶——在人 CCA 组织中。目前正在其他恶性肿瘤临床试验中测试的 PRMT5 靶向药物在人类 CCA 细胞系和类器官以及两种免疫功能正常的 CCA 小鼠模型中进行了评估。进行转录组学、蛋白质组学和功能分析以探索潜在的抗肿瘤机制。结果 PRMT5 和 MEP50 蛋白在大多数 CCA 组织中相对过表达。25% 的肝内 CCA 不存在 MTAP。PRMT5 靶向药物显着抑制 CCA 细胞增殖，与顺铂和吉西他滨协同作用，并阻碍胆管癌类器官的生长。PRMT5 抑制减弱了参与染色质重塑和 DNA 修复的致癌基因的表达，持续诱导 RNA 环的形成并促进 DNA 损伤。用 PRMT5 靶向药物治疗显着抑制了实验性 CCA 的生长，而没有不良反应，并同时诱导 CD4 和 CD8 T 细胞募集到缩小的肿瘤病灶。结论 PRMT5 和 MEP50 在人 CCA 中经常上调，PRMT5 靶向药物在临床相关 CCA 模型中具有显著的抗肿瘤疗效。 我们的研究结果支持在临床试验中评估 PRMT5 抑制剂，包括它们与细胞毒性和免疫疗法的联合治疗。数据可应合理要求提供。