{"title":"Time for arginine methylation: PRMT5 inhibition to advance cholangiocarcinoma treatment","authors":"Romain Désert, Lipika Goyal, Thomas F Baumert","doi":"10.1136/gutjnl-2024-333632","DOIUrl":null,"url":null,"abstract":"Cholangiocarcinoma (CCA) is a highly aggressive adenocarcinoma of the biliary tract system with unsatisfactory therapeutic options.1 Standard frontline treatment for unresectable or metastatic CCA consisting of cisplatin and gemcitabine combined with checkpoint inhibitors targeting programmed cell death ligand 1 or programmed cell death 1 offers objective response rates of less than 30% and a median survival of approximately a year.1 Targeted therapies against FGFR2 fusions and IDH1 mutations have gained regulatory approval in CCA, but these are applicable only in a minority of patients.1 Disease-agnostic approvals of therapies targeting HER2 overexpression, NTRK fusions, RET fusions and microsatellite-unstable tumours also benefit patients with CCA, but again, only a small minority. Therefore, novel strategies to treat CCA are urgently needed. Molecular heterogeneity stands as a major barrier to improving outcomes in CCA. Genetic alterations in DNA only explain a part of this heterogeneity. A rising number of studies suggest a major role for epigenetic perturbations in controlling CCA fate.2 Indeed, epigenetic vulnerabilities including histone modifications have been suggested as novel CCA targets.1 An example of a histone regulator is the protein arginine methyltransferase 5 (PRMT5). PRMT5 forms a homotetramer that associates with methylosome protein 50 (MEP50) in a highly active complex that exhibits high affinity for arginine residues. Via histone methylation, PRMT5 functions as a transcriptional co-repressor supporting gene expression of oncogenic signalling via regulation of genes such as p53, NFκB or p21.2 In addition, PRMT5 regulates splicing via its role as the enzymatic component of the methylosome, a multi-subunit complex containing MEP50, facilitating small nuclear ribonucleoprotein assembly (figure 1). PRMT5 and MEP50 functions have been shown to be important in regulating genome stability and DNA repair.3 Preclinical studies of PRMT5 inhibitors have shown antitumour activity …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"9 1","pages":""},"PeriodicalIF":23.0000,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gut","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/gutjnl-2024-333632","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive adenocarcinoma of the biliary tract system with unsatisfactory therapeutic options.1 Standard frontline treatment for unresectable or metastatic CCA consisting of cisplatin and gemcitabine combined with checkpoint inhibitors targeting programmed cell death ligand 1 or programmed cell death 1 offers objective response rates of less than 30% and a median survival of approximately a year.1 Targeted therapies against FGFR2 fusions and IDH1 mutations have gained regulatory approval in CCA, but these are applicable only in a minority of patients.1 Disease-agnostic approvals of therapies targeting HER2 overexpression, NTRK fusions, RET fusions and microsatellite-unstable tumours also benefit patients with CCA, but again, only a small minority. Therefore, novel strategies to treat CCA are urgently needed. Molecular heterogeneity stands as a major barrier to improving outcomes in CCA. Genetic alterations in DNA only explain a part of this heterogeneity. A rising number of studies suggest a major role for epigenetic perturbations in controlling CCA fate.2 Indeed, epigenetic vulnerabilities including histone modifications have been suggested as novel CCA targets.1 An example of a histone regulator is the protein arginine methyltransferase 5 (PRMT5). PRMT5 forms a homotetramer that associates with methylosome protein 50 (MEP50) in a highly active complex that exhibits high affinity for arginine residues. Via histone methylation, PRMT5 functions as a transcriptional co-repressor supporting gene expression of oncogenic signalling via regulation of genes such as p53, NFκB or p21.2 In addition, PRMT5 regulates splicing via its role as the enzymatic component of the methylosome, a multi-subunit complex containing MEP50, facilitating small nuclear ribonucleoprotein assembly (figure 1). PRMT5 and MEP50 functions have been shown to be important in regulating genome stability and DNA repair.3 Preclinical studies of PRMT5 inhibitors have shown antitumour activity …
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.