逆转肿瘤治疗耐药——基于热休克蛋白90视角的机制与药物研发前沿

Reversing Tumor Therapy Resistance—Mechanistic Insights from Heat Shock Protein 90 and Frontiers in Drug Development

摘要

肿瘤治疗耐药性已成为当前临床面临的主要挑战，约 90% 的癌症相关死亡与其密切相关。热休克蛋白 90（heat shock protein 90, HSP90）作为分子伴侣系统的核心组分，通过稳定多种致癌客户蛋白、激活代偿信号通路、促进 DNA 修复、调控肿瘤免疫及代谢重编程等多重机制，成为介导肿瘤耐药的关键分子。系统综述 HSP90 在肿瘤耐药中的作用机制，并深入探讨靶向 HSP90 的药物研发策略与前沿进展，涵盖传统 N 端 ATP 竞争性抑制剂、C 端抑制剂、亚型选择性抑制剂、双靶点抑制剂，以及诸如靶向 HSP90-共伴侣蛋白相互作用、分子伴侣保留效应药物缀合物和分子伴侣介导的蛋白降解剂等新兴策略，旨在为克服肿瘤治疗耐药提供新的理论依据和策略方向。

Abstract

Tumor therapy resistance has emerged as a major challenge in clinical oncology, and is closely associated with approximately 90% of cancer-related deaths. Heat shock protein 90 (HSP90), a central component of the molecular chaperone system, serves as a key mediator in drug resistance through diverse mechanisms. These include stabilizing oncogenic client proteins, activating compensatory signaling pathways, promoting DNA repair, modulating tumor immunity, and facilitating metabolic reprogramming. This article systematically reviews the involvement of HSP90 in tumor therapy resistance and explores recent advances in HSP90-targeted drug development strategies. These encompass traditional N-terminal ATP-competitive inhibitors, C-terminal inhibitors, isoform-selective inhibitors, dual-target inhibitors, as well as emerging approaches such as targeting HSP90-co-chaperone interactions, chaperone-retention effect drug conjugates (CREDC), and chaperone-mediated protein degraders. Together, these strategies aim to provide new theoretical foundations and strategic directions for overcoming tumor therapy resistance.

关键词

肿瘤耐药 / 热休克蛋白 90 / 分子伴侣抑制剂 / 蛋白相互作用 / 成药性优化

Key words

tumor therapy resistance / heat shock protein 90 / molecular chaperone inhibitors / protein-protein interaction / druggability optimization

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基金资助

国家自然科学基金资助项目(82274000)

国家自然科学基金资助项目(82173849)

国家自然科学基金青年项目(82103985)