Butler Lisa M, Ferraldeschi Roberta, Armstrong Heather K, Centenera Margaret M, Workman Paul
School of Medicine and Freemasons Foundation Centre for Men's Health, University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, Australia.
The Institute of Cancer Research, London, United Kingdom. Royal Marsden NHS Foundation Trust, London, United Kingdom.
Mol Cancer Res. 2015 Nov;13(11):1445-51. doi: 10.1158/1541-7786.MCR-15-0234. Epub 2015 Jul 28.
HSP90 is required for maintaining the stability and activity of a diverse group of client proteins, including protein kinases, transcription factors, and steroid hormone receptors involved in cell signaling, proliferation, survival, oncogenesis, and cancer progression. Inhibition of HSP90 alters the HSP90-client protein complex, leading to reduced activity, misfolding, ubiquitination, and, ultimately, proteasomal degradation of client proteins. HSP90 inhibitors have demonstrated significant antitumor activity in a wide variety of preclinical models, with evidence of selectivity for cancer versus normal cells. In the clinic, however, the efficacy of this class of therapeutic agents has been relatively limited to date, with promising responses mainly observed in breast and lung cancer, but no major activity seen in other tumor types. In addition, adverse events and some significant toxicities have been documented. Key to improving these clinical outcomes is a better understanding of the cellular consequences of inhibiting HSP90 that may underlie treatment response or resistance. This review considers the recent progress that has been made in the study of HSP90 and its inhibitors and highlights new opportunities to maximize their therapeutic potential.
热休克蛋白90（HSP90）对于维持多种客户蛋白的稳定性和活性至关重要，这些客户蛋白包括参与细胞信号传导、增殖、存活、肿瘤发生和癌症进展的蛋白激酶、转录因子和类固醇激素受体。抑制HSP90会改变HSP90-客户蛋白复合物，导致客户蛋白活性降低、错误折叠、泛素化，并最终被蛋白酶体降解。HSP90抑制剂在多种临床前模型中已显示出显著的抗肿瘤活性，有证据表明其对癌细胞与正常细胞具有选择性。然而，在临床上，这类治疗药物的疗效迄今为止相对有限，主要在乳腺癌和肺癌中观察到有前景的反应，但在其他肿瘤类型中未见明显活性。此外，还记录了不良事件和一些显著的毒性。改善这些临床结果的关键在于更好地理解抑制HSP90可能作为治疗反应或耐药基础的细胞后果。本综述考虑了HSP90及其抑制剂研究的最新进展，并强调了最大化其治疗潜力的新机会。
