Kim Yeongbeom, Lim Su Yeon, Kim Hyun-Ouk, Ha Suk-Jin, Park Jeong-Ann, Won Young-Wook, Chae Sehyun, Lim Kwang Suk
Department of Smart Health Science and Technology, Kangwon National University, Chuncheon 24341, Republic of Korea.
Department of Biotechnology and Bioengineering, College of ACE, Kangwon National University, Chuncheon 24341, Republic of Korea.
Pharmaceuticals (Basel). 2025 Jul 22;18(8):1083. doi: 10.3390/ph18081083.
Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, their therapeutic potential as monotherapies has been limited by suboptimal efficacy, dose-limiting toxicity, and the emergence of drug resistance. Recent studies have demonstrated that combination therapies involving HSP90 inhibitors and other anticancer agents such as chemotherapeutics, targeted therapies, and immune checkpoint inhibitors can enhance anticancer activity, overcome resistance mechanisms, and modulate the tumor microenvironment. These synergistic effects are mediated by the concurrent degradation of client proteins, the disruption of signaling pathways, and the enhancement of antitumor immunity. However, the successful clinical implementation of such combination strategies requires the careful optimization of dosage, administration schedules, toxicity management, and patient selection based on predictive biomarkers. In this review, we provide a comprehensive overview of the mechanistic rationale, preclinical and clinical evidence, and therapeutic challenges associated with HSP90 inhibitor-based combination therapies. We also discuss future directions leveraging emerging technologies including multi-omics profiling, artificial intelligence, and nanoparticle-mediated delivery for the development of personalized and effective combination regimens in oncology.
热休克蛋白90（HSP90）是一种分子伴侣，在众多对癌细胞存活和增殖至关重要的癌蛋白及信号分子的稳定化和功能激活中发挥关键作用。尽管HSP90抑制剂已得到广泛研发和临床评估，但其作为单一疗法的治疗潜力受到疗效欠佳、剂量限制性毒性和耐药性出现的限制。近期研究表明，涉及HSP90抑制剂与其他抗癌药物（如化疗药物、靶向疗法和免疫检查点抑制剂）的联合疗法可增强抗癌活性、克服耐药机制并调节肿瘤微环境。这些协同效应是由客户蛋白的同时降解、信号通路的破坏以及抗肿瘤免疫力的增强介导的。然而，此类联合策略的成功临床应用需要基于预测性生物标志物对剂量、给药方案、毒性管理和患者选择进行仔细优化。在本综述中，我们全面概述了基于HSP90抑制剂的联合疗法的作用机制原理、临床前和临床证据以及治疗挑战。我们还讨论了利用多组学分析、人工智能和纳米颗粒介导递送等新兴技术开发个性化有效联合方案在肿瘤学中的未来方向。
