靶向蛋白质泛素修饰及降解在前列腺癌治疗中的机遇与挑战

前列腺癌是中国发病率增长最快的男性肿瘤，抗雄激素治疗耐药是导致前列腺癌患者预后差的主要原因。因此，解决耐药性难题是前列腺癌转化研究的关键问题。哺乳动物细胞利用泛素-蛋白酶体系统实现蛋白质的靶向降解。因此，前列腺癌中关键的癌基因如雄激素受体（AR）的上游泛素化调控因子（如去泛素化酶）是潜在的治疗靶点。然而，这些酶具有较广的底物谱系，存在脱靶的可能性。近来，基于泛素-蛋白酶体系统开发的蛋白质降解靶向嵌合体（proteolysis-targeting chimeras,PROTAC）技术是最具前景和革命性的新型抗癌药物研发技术，能够利用特定E3泛素连接酶对靶蛋白进行降解而不影响其他底物。与传统小分子抑制剂相比，PROTAC分子在克服耐药性以及针对不可成药的靶点方面拥有巨大优势。目前，针对AR的PROTAC降解剂已在II期临床取得了成功，靶向蛋白质泛素化及降解途径的新技术将有望为前列腺癌的临床治疗带来新的突破。

Opportunities and Challenges in Targeting Ubiquitin Modification and Degradation for Prostate Cancer Therapy

Prostate cancer is the fastest growing cancer among Chinese male population. Resistance to antiandrogen therapy is the leading cause of death in patients with prostate cancer. Therefore, solving the drug resistance conundrum is the key issue for translational research in prostate cancer. Mammalian cells utilize the ubiquitin-proteasome system to degrade targeted proteins. Consequently, key oncogenes in prostate cancer, such as upstream ubiquitination regulators (e.g., deubiquitinases) of androgen receptor (AR), are potential therapeutic targets. However, these enzymes have a broad spectrum of substrates and may be off target. Recently, the proteolysis-targeting chimeras (PROTAC) technology developed based on the ubiquitin-proteasome system is the most promising and revolutionary new anti-cancer drug discovery technology, enabling the degradation of target proteins by specific E3 ubiquitin ligases without affecting other substrates. Compared with traditional small molecule inhibitors, PROTAC hold great advantages in overcoming drug resistance as well as targeting undruggable targets. Currently, the PROTAC degraders targeting the AR has achieved success in phase II clinical trials. In the future, the new technology targeting protein ubiquitination and degradation pathway will bring new breakthroughs for the clinical treatment of prostate cancer.