调控蛋白质稳态的抗肿瘤新靶点和新策略研究进展

蛋白质稳态失调与恶性肿瘤等多种重大疾病密切相关。造成蛋白质稳态失调的原因包括蛋白质合成改变、蛋白质折叠与翻译后修饰异常、泛素-蛋白酶体系统或自噬-溶酶体系统等蛋白质降解途径紊乱等。近年来，大量研究表明蛋白质稳态失调可引起内质网应激及线粒体等重要细胞器功能异常，并导致促癌蛋白异常累积或抑癌蛋白过度降解，进而促进肿瘤发生发展。鉴于蛋白质稳态非常广泛地涉及肿瘤恶性演进的各个阶段，因此基于蛋白质稳态调控的关键机制或重要功能蛋白发展的靶向干预策略，是重要的抗肿瘤药物研发思路。其中靶向蛋白酶体、E3泛素连接酶的药物已成功上市用于多发性骨髓瘤等恶性肿瘤的治疗，而一系列蛋白降解技术如蛋白水解靶向嵌合体（proteolysis-targeting chimera，PROTAC）、溶酶体靶向嵌合体（lysosome-targeting chimera，LYTAC）等也已成为具有前景的新兴抗肿瘤策略。综述围绕蛋白质稳态调控领域，总结了一系列抗肿瘤靶点和策略的研究进展以及目前已上市或处于临床研究阶段的（候选）药物、靶点和适应证，为深入了解和认识蛋白质稳态调控机制，进一步拓展其在肿瘤治疗中的应用提供思路和参考。

Research Progress of New Targets and Strategies to Regulate Proteostasis in Cancer

Proteostasis deregulation, which is closely related to malignant tumors and other major diseases, is caused by such factors as altered protein synthesis, abnormal protein folding and post-translational modifications, as well as the deregulation of protein degradation pathways like the ubiquitin-proteasome system or the autophagy-lysosomal system. In recent years, plenty of studies have shown that proteostasis deregulation may result in endoplasmic reticulum stress and abnormal function of important organelles such as mitochondria, thus leading to abnormal accumulation of oncoprotein or excessive degradation of tumor suppressor protein and further promoting tumorigenesis. Since proteostasis is extensively involved in various stages of tumor malignancy, intervention strategies based on the key molecular mechanisms or crucial functional proteins of proteostasis regulation are important areas in anti-tumor drug research and development. Drugs targeting proteasomes and E3 ubiquitin ligases have been clinically utilized for the treatment of multiple myeloma, and a series of protein degradation technologies such as proteolysis-targeting chimera (PROTAC) and lysosome-targeting chimera (LYTAC) have emerged as promising strategies. This article reviews the research progress in the areas of proteostasis regulation, and summarizes the (candidate) drugs, targets and indications that have been approved or are under clinical research, in an attempt to provide some insight and reference for an in-depth understanding of proteostasis regulation mechanisms and further expansion of their application in cancer treatment.