Jasmin Elurbide, Leticia Colyn, Maria U Latasa, Iker Uriarte, Stefano Mariani, Amaya Lopez-Pascual, Emiliana Valbuena, Borja Castello-Uribe, Robert Arnes-Benito, Elena Adan-Villaescusa, Luz A Martinez-Perez, Mikel Azkargorta, Felix Elortza, Hanghang Wu, Marcin Krawczyk, Kai Markus Schneider, Bruno Sangro, Luca Aldrighetti, Francesca Ratti, Andrea Casadei Gardini, Jose J G Marin, Irene Amat, Jesus M Urman, Maria Arechederra, Maria Luz Martinez-Chantar, Christian Trautwein, Meritxell Huch, Francisco Javier Cubero, Carmen Berasain, Maite G Fernandez-Barrena, Matias A Avila
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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.","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":23.0000,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of PRMT5 as a therapeutic target in cholangiocarcinoma\",\"authors\":\"Jasmin Elurbide, Leticia Colyn, Maria U Latasa, Iker Uriarte, Stefano Mariani, Amaya Lopez-Pascual, Emiliana Valbuena, Borja Castello-Uribe, Robert Arnes-Benito, Elena Adan-Villaescusa, Luz A Martinez-Perez, Mikel Azkargorta, Felix Elortza, Hanghang Wu, Marcin Krawczyk, Kai Markus Schneider, Bruno Sangro, Luca Aldrighetti, Francesca Ratti, Andrea Casadei Gardini, Jose J G Marin, Irene Amat, Jesus M Urman, Maria Arechederra, Maria Luz Martinez-Chantar, Christian Trautwein, Meritxell Huch, Francisco Javier Cubero, Carmen Berasain, Maite G Fernandez-Barrena, Matias A Avila\",\"doi\":\"10.1136/gutjnl-2024-332998\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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. 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引用次数: 0
摘要
背景 胆管癌(CCA)是一种非常难以治疗的癌症。化疗几乎无效,而免疫检查点抑制剂的反应也很有限。因此,需要找到新的治疗策略。目的 我们研究了精氨酸甲基转移酶5(PRMT5)作为CCA新治疗靶点的特性。设计 我们评估了人 CCA 组织中 PRMT5、其功能伙伴 MEP50 和甲硫腺苷磷酸化酶(MTAP)的表达情况,MTAP 可调节 PRMT5 对药物抑制剂的敏感性。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 细胞系和器官组织以及两种免疫功能正常的 CCA 小鼠模型中进行了评估。研究人员进行了转录组、蛋白质组和功能分析,以探索潜在的抗肿瘤机制。结果 PRMT5 和 MEP50 蛋白在大多数 CCA 组织中相关性过表达。25% 的肝内 CCA 不存在 MTAP。PRMT5靶向药物能显著抑制CCA细胞增殖,与顺铂和吉西他滨协同作用,并阻碍胆管癌组织细胞的生长。抑制PRMT5会减弱参与染色质重塑和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。使用 PRMT5 靶向药物治疗可明显抑制实验性 CCA 的生长,且无不良反应,同时还能诱导 CD4 和 CD8 T 细胞招募到缩小的肿瘤病灶中。结论 PRMT5和MEP50在人类CCA中经常上调,PRMT5靶向药物在临床相关的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,包括将其与细胞毒疗法和免疫疗法相结合。如有合理要求,可提供相关数据。
Identification of PRMT5 as a therapeutic target in cholangiocarcinoma
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.
期刊介绍:
Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts.
As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.