Background: Targeted therapies have been largely ineffective against glioblastoma (GBM) owing to the tumor’s heterogeneity and intrinsic and adaptive treatment resistance. Targeting multiple pro-survival pathways simultaneously may overcome these limitations and yield effective treatments. Heat shock protein 90 (HSP90), an essential component of the epichaperome complex, is critical for the proper folding and activation of several pro-survival oncogenic proteins that drive GBM biology. Methods: Using a panel of biochemical and biological assays, we assessed the expression of HSP90 and its downstream targets and the effects of PU-H71, a highly specific and potent HSP90 inhibitor, on target modulation, downstream biochemical alterations, cell cycle progression, proliferation, migration, and apoptosis in patient-derived glioma stem-like cells (GSCs) with molecular profiles characteristic of GBM, as well as commercial glioma cell lines and normal human astrocytes (NHAs). Results: HSP90 inhibition by PU-H71 in GSCs significantly reduced cell proliferation, colony formation, wound healing, migration, and angiogenesis. In glioma cells, but not NHAs, potent PU-H71-mediated HSP90 inhibition resulted in the downregulation of pro-survival client proteins such as EGFR, MAPK, AKT, and S6. This reduction in pro-survival signals increased glioma cells’ sensitivity to temozolomide, a monofunctional alkylator, and the combination of PU-H71 and temozolomide had greater anticancer efficacy than either agent alone. Conclusions: These results confirm that HSP90 is a strong pro-survival factor in molecularly heterogeneous gliomas and suggest that epichaperome inhibition with HSP90 inhibitors warrants further investigation for the treatment of gliomas.
背景：由于胶质母细胞瘤（GBM）的异质性以及内在和适应性治疗抵抗，靶向疗法对其效果有限。同时靶向多个促生存通路可能克服这些限制并产生有效治疗。热休克蛋白90（HSP90）作为表分子伴侣复合体的关键组分，对驱动GBM生物学行为的多种促生存致癌蛋白的正确折叠和激活至关重要。方法：通过一系列生化和生物学检测，我们评估了HSP90及其下游靶点的表达情况，以及高特异性强效HSP90抑制剂PU-H71对具有GBM分子特征的患者源性胶质瘤干细胞样细胞（GSCs）、商用胶质瘤细胞系及正常人星形胶质细胞（NHAs）中靶点调控、下游生化改变、细胞周期进程、增殖、迁移和凋亡的影响。结果：在GSCs中，PU-H71对HSP90的抑制显著降低了细胞增殖、集落形成、伤口愈合、迁移和血管生成。在胶质瘤细胞（而非NHAs）中，强效的PU-H71介导的HSP90抑制导致EGFR、MAPK、AKT和S6等促生存客户蛋白下调。这种促生存信号的减弱增加了胶质瘤细胞对单功能烷化剂替莫唑胺的敏感性，且PU-H71与替莫唑胺联用比任一单药具有更强的抗癌效力。结论：这些结果证实HSP90是分子异质性胶质瘤的重要促生存因子，并提示通过HSP90抑制剂抑制表分子伴侣复合体值得作为胶质瘤治疗策略进一步深入研究。
肿瘤(癌症)患者之家