School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016, China.
School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dagong Road 2, Panjin, 124221, China.
Arch Pharm Res. 2024 May;47(5):442-464. doi: 10.1007/s12272-024-01494-1. Epub 2024 Apr 17.
The molecular chaperone heat shock protein 90 (HSP90) regulates multiple crucial signalling pathways in cancer by driving the maturation of key signalling components, thereby playing a crucial role in tumorigenesis and drug resistance in cancer. Inhibition of HSP90 results in metastable conformational collapse of its client proteins and their proteasomal degradation. Considerable efforts have been devoted to the development of small-molecule inhibitors targeting HSP90, and more than 20 inhibitors have been evaluated in clinical trials for cancer therapy. However, owing to disadvantages such as organ toxicity and drug resistance, only one HSP90 inhibitor has been approved for use in clinical settings. In recent years, HSP90 inhibitors used in combination with other anti-cancer therapies have shown remarkable potential in the treatment of cancer. HSP90 inhibitors work synergistically with various anti-cancer therapies, including chemotherapy, targeted therapy, radiation therapy and immunotherapy. HSP90 inhibitors can improve the pharmacological effects of the above-mentioned therapies and reduce treatment resistance. This review provides an overview of the use of combination therapy with HSP90 inhibitors and other anti-cancer therapies in clinical and preclinical studies reported in the past decade and summarises design strategies and prospects for these combination therapies. Altogether, this review provides a theoretical basis for further research and application of these combination therapies in the treatment of cancer.
分子伴侣热休克蛋白 90（HSP90）通过驱动关键信号成分的成熟，调节癌症中的多个关键信号通路，从而在癌症的发生和耐药性中发挥关键作用。HSP90 的抑制导致其客户蛋白的亚稳构象崩溃和蛋白酶体降解。人们投入了大量精力开发针对 HSP90 的小分子抑制剂，已有 20 多种抑制剂在癌症治疗的临床试验中进行了评估。然而，由于器官毒性和耐药性等缺点，只有一种 HSP90 抑制剂被批准用于临床。近年来，HSP90 抑制剂与其他抗癌疗法联合使用在癌症治疗中显示出巨大的潜力。HSP90 抑制剂与各种抗癌疗法（包括化疗、靶向治疗、放射治疗和免疫治疗）协同作用。HSP90 抑制剂可以提高上述疗法的药理作用并降低治疗耐药性。本文综述了过去十年中 HSP90 抑制剂与其他抗癌疗法联合应用于临床和临床前研究的情况，并总结了这些联合疗法的设计策略和前景。总的来说，本文为这些联合疗法在癌症治疗中的进一步研究和应用提供了理论基础。
