Sharma Pratibha, Xu Jihong, Puduvalli Vinay K
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Cancers (Basel). 2024 Nov 24;16(23):3934. doi: 10.3390/cancers16233934.
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.
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).
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.
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.
由于胶质母细胞瘤（GBM）的肿瘤异质性以及内在和适应性治疗抗性，靶向治疗在很大程度上对其无效。同时靶向多种促生存途径可能克服这些限制并产生有效的治疗方法。热休克蛋白90（HSP90）是表观伴侣蛋白复合物的重要组成部分，对于驱动GBM生物学的几种促生存致癌蛋白的正确折叠和激活至关重要。
我们使用一系列生化和生物学检测方法，评估了HSP90及其下游靶点的表达，以及高度特异性和强效的HSP90抑制剂PU-H71对具有GBM分子特征的患者来源的胶质瘤干细胞样细胞（GSCs）、商业胶质瘤细胞系和正常人星形胶质细胞（NHAs）中靶点调节、下游生化改变、细胞周期进程、增殖、迁移和凋亡的影响。
PU-H71对GSCs中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。在胶质瘤细胞中，而非NHAs中，强效的PU-H71介导的HSP90抑制导致促生存客户蛋白如表皮生长因子受体（EGFR）、丝裂原活化蛋白激酶（MAPK）、蛋白激酶B（AKT）和核糖体蛋白S6（S6）的下调。这种促生存信号的减少增加了胶质瘤细胞对单功能烷化剂替莫唑胺的敏感性，并且PU-H71与替莫唑胺联合使用比单独使用任一药物具有更强的抗癌疗效。
这些结果证实HSP90是分子异质性胶质瘤中的一个强大的促生存因子，并表明用HSP90抑制剂抑制表观伴侣蛋白复合物值得进一步研究用于胶质瘤的治疗。
