前列腺癌内分泌治疗抵抗机制的研究进展  

Research progress on mechanisms of endocrine therapy resistance in prostate cancer

作　　者：戚子昊 王雷杰 吴林杰 白小杰 樊九铭 王天堃 韩雨桐 于营 郭中强[3] 曾宪涛 QI Zihao;WANG Leijie;WU Linjie;BAI Xiaojie;FAN Jiuming;WANG Tiankun;HAN Yutong;YU Ying;GUO Zhongqiang;ZENG Xiantao(School of Clinical Medicine,Henan University,Kaifeng 475004,Henan Province,China;Center for Evidence-Based and Translational Medicine,Zhongnan Hospital of Wuhan University,Wuhan 430071,China;Department of Urology,Zhongnan Hospital of Wuhan University,Wuhan 430071,China)

机构地区：[1]河南大学医学院,河南开封475004 [2]武汉大学中南医院循证与转化医学中心,武汉430071 [3]武汉大学中南医院泌尿外科,武汉430071

出　　处：《医学新知》2025年第4期452-460,共9页New Medicine

基　　金：国家自然科学基金面上项目(8217113347);国家自然科学基金青年科学基金项目(82403905)。

摘　　要：前列腺癌(prostate cancer,PCa)是全球男性中发病率最高的恶性肿瘤之一,也是导致肿瘤相关性死亡的重要原因之一。PCa是依赖于雄激素的男性生殖系统肿瘤,雄激素剥夺治疗和第二代雄激素受体拮抗剂(如恩杂鲁胺和阿帕他胺)显著延长了患者的无进展生存期,但大多数患者治疗后会发展为去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC),对药物产生耐药性。CRPC的耐药机制具有生物复杂性,其中包括雄激素受体(androgen receptor,AR)信号轴异常、DNA修复缺陷、肿瘤微环境变化及代谢重编程等。近年来,针对这些机制的靶向治疗策略取得了重要进展,如PARP抑制剂(如奥拉帕利)对DNA修复缺陷患者具有显著疗效,PROTAC技术通过降解AR及其变异体逆转了AR信号通路异常激活诱导的去势抵抗。本文系统阐述了CRPC的主要耐药机制,深入探讨了靶向治疗和免疫治疗在CRPC中的最新进展,并展望未来通过多学科交叉、多靶点联合治疗以逆转PCa去势抵抗的潜力,为CPRC的治疗策略和治疗靶点开发提供参考。Prostate cancer(PCa)is one of the most prevalent malignancies among men worldwide and a leading cause of cancer-related deaths.As an androgen-dependent tumor of the male reproductive system,PCa initially responds well to androgen deprivation therapy(ADT)and second-generation androgen receptor(AR)antagonists(enzalutamide and apalutamide),which significantly extend progression-free survival.However,Most patients would developed into castration-resistant prostate cancer(CRPC),resulting in the resistant to ADT.The mechanisms driving resistance to novel endocrine therapies exhibit biological complexity,including abnormalities in the AR signaling axis,defects in DNA damage repair,alterations in the tumor microenvironment,and metabolic reprogramming.In recent years,important advances have been made in targeted therapeutic strategies.For instance,PARP inhibitors(olaparib)have demonstrated remarkable efficacy in patients with defects in DNA damage repair,PROTAC technology has shown potential in reversing castration resistance by degrading AR and its variants,thereby countering aberrant activation of the AR signaling pathway.This review systematically elucidates the major resistance mechanisms of CRPC,explores the latest advances in targeted and immunotherapy for CRPC,and envisions the potential of multidisciplinary,multi-target combination therapies to reverse castration resistance in PCa,providing novel therapeutic strategies and targets for CRPC.

关 键 词：前列腺癌 雄激素受体 雄激素剥夺治疗 去势抵抗 耐药机制 

分 类 号：R737.25[医药卫生—肿瘤]