文章：

整合多组学分析揭示Hsp90β选择性抑制的耐药机制

Integrative Multi-Omics Analyses Reveal Mechanisms of Resistance to Hsp90β-Selective Inhibition

原文发布日期：30 October 2025

DOI: 10.3390/cancers17213488

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Targeting Hsp90β with isoform-selective inhibitors offers a promising therapeutic strategy with reduced toxicity compared to pan-Hsp90 inhibition. However, mechanisms of resistance to Hsp90β-selective inhibition remain poorly defined. This study aimed to identify molecular determinants of Hsp90β dependency and pharmacologic resistance across cancer types. Methods: We integrated gene dependency, transcriptomic, proteomic, metabolomic, and drug sensitivity data from the Cancer Cell Line Encyclopedia with in vitro validation using the Hsp90β-selective inhibitor, NDNB-25. Comparative and correlation analyses were performed to identify resistance-associated pathways, followed by network and combination drug testing to validate functional interactions. Results: Resistant cell lines exhibited extensive rewiring of Rho GTPase signaling, cytoskeletal remodeling, and metabolic adaptation, including mitochondrial dysfunction and redox imbalance. Integrated analyses linked these phenotypes to aryl hydrocarbon receptor (AHR) activation and compensatory Hsp90α expression. Experimental validation confirmed increased kynurenine levels, a known endogenous AHR ligand, in NDNB-25–acquired resistant cells. Gene–drug network integration revealed collateral sensitivity to carboplatin, which synergized with Hsp90β inhibition in resistant models. Conclusions: This study defines the molecular features and adaptive programs underlying resistance to Hsp90β-selective inhibition and identifies therapeutic vulnerabilities that can be exploited to overcome it. The findings establish a systems-level framework for predicting Hsp90β inhibitor response and support rational combination strategies, including carboplatin co-treatment, for future preclinical development.

摘要翻译： 

背景/目的：与泛Hsp90抑制相比，采用亚型选择性抑制剂靶向Hsp90β是一种前景广阔且毒性更低的治疗策略。然而，针对Hsp90β选择性抑制的耐药机制仍不明确。本研究旨在揭示不同癌症类型中Hsp90β依赖性及药理学耐药性的分子决定因素。方法：我们整合了癌细胞系百科全书中的基因依赖性、转录组学、蛋白质组学、代谢组学和药物敏感性数据，并利用Hsp90β选择性抑制剂NDNB-25进行体外验证。通过比较分析和相关性分析识别耐药相关通路，随后进行网络分析和联合药物测试以验证功能相互作用。结果：耐药细胞系表现出Rho GTPase信号传导、细胞骨架重塑和代谢适应（包括线粒体功能障碍和氧化还原失衡）的广泛重编程。整合分析将这些表型与芳香烃受体激活及Hsp90α代偿性表达相关联。实验验证证实NDNB-25获得性耐药细胞中犬尿氨酸（一种已知的内源性AHR配体）水平升高。基因-药物网络整合揭示了其对卡铂的附带敏感性，该药物在耐药模型中与Hsp90β抑制具有协同作用。结论：本研究阐明了Hsp90β选择性抑制耐药的分子特征和适应性调控程序，并识别了可用于克服耐药的治疗脆弱点。这些发现建立了一个预测Hsp90β抑制剂反应的系统水平框架，并为包括卡铂联合治疗在内的合理联合策略提供了临床前开发依据。

原文链接：

Integrative Multi-Omics Analyses Reveal Mechanisms of Resistance to Hsp90β-Selective Inhibition