Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance.

1. Drug Resist Updat. 2024 Jan;72:101016. doi: 10.1016/j.drup.2023.101016. Epub 2023 Nov 3. Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance. Zhu Y(1), Xia T(2), Chen DQ(3), Xiong X(2), Shi L(1), Zuo Y(4), Xiao H(5), Liu L(6). Author information: (1)Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China. (2)Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. (3)Department of Medicine Oncology, Shenzhen Longhua District Central Hospital, Shenzhen 518110, China. (4)Shaanxi Key Laboratory of Brain Disorders, Institute of Basic Translational Medicine, Xi'an Medical University, Xi'an 710021, China. Electronic address: zuoyueqi_jzs@xiyi.edu.cn. (5)Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China. Electronic address: xiaohongtao@scszlyy.org.cn. (6)Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: liuli@swmu.edu.cn. Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic arginine methylation, which regulates various biological and pathological processes, as a result, they are attractive therapeutic targets for overcoming anti-cancer drug resistance. The ongoing development of small molecules targeting PRMTs has resulted in the generation of chemical probes for modulating most PRMTs and facilitated clinical treatment for the most advanced oncology targets, including PRMT1 and PRMT5. In this review, we summarize various mechanisms underlying protein arginine methylation and the roles of specific PRMTs in driving cancer drug resistance. Furthermore, we highlight the potential clinical implications of PRMT inhibitors in decreasing cancer drug resistance. PRMTs promote the formation and maintenance of drug-tolerant cells via several mechanisms, including altered drug efflux transporters, autophagy, DNA damage repair, cancer stem cell-related function, epithelial-mesenchymal transition, and disordered tumor microenvironment. Multiple preclinical and ongoing clinical trials have demonstrated that PRMT inhibitors, particularly PRMT5 inhibitors, can sensitize cancer cells to various anti-cancer drugs, including chemotherapeutic, targeted therapeutic, and immunotherapeutic agents. Combining PRMT inhibitors with existing anti-cancer strategies will be a promising approach for overcoming anti-cancer drug resistance. Furthermore, enhanced knowledge of the complex functions of arginine methylation and PRMTs in drug resistance will guide the future development of PRMT inhibitors and may help identify new clinical indications. Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved. DOI: 10.1016/j.drup.2023.101016 PMID: 37980859 [Indexed for MEDLINE] Conflict of interest statement: Declaration of Competing Interest The researchers state that this investigation was carried out without any business or monetary connections that could be interpreted as possible conflicts of interest.