ArticleCancers2025
Integrative Multi-Omics Analyses Reveal Mechanisms of Resistance to Hsp90β-Selective Inhibition.
Article in Cancers, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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Who cites it
3 citing papers in PubMed.
- Evolution of Hsp90 targeting: From stress biology to clinical translation.Cell stress & chaperones · 2026Review
- Attempts to Achieve Targeted Covalent Inhibition of Hsp90β.Chemical biology & drug design · 2026Article
- Multi-omic integration identifies broad drug resistance mechanisms and strategies to therapeutically reprogram cancer cells.iScience · 2026Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
BACKGROUND/
objectivesTargeting 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.
methodsWe 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.
resultsResistant 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.
conclusionsThis 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.
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Registered trials
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