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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Targeting Heat Shock Protein 90 beta (Hsp90β) with isoform-selective inhibitors presents a therapeutic strategy with potentially lower toxicity than pan-Hsp90 inhibition.
• Understanding resistance mechanisms to Hsp90β-selective inhibitors is crucial for effective clinical application.

Purpose of the Study:

• To identify molecular factors driving Hsp90β dependency and resistance to its selective inhibitors across diverse cancer types.
• To define adaptive programs that confer pharmacologic resistance to Hsp90β-targeted therapies.

Main Methods:

• Integrated analysis of multi-omics data (gene dependency, transcriptomics, proteomics, metabolomics, drug sensitivity) from the Cancer Cell Line Encyclopedia.
• In vitro validation using the Hsp90β-selective inhibitor NDNB-25, comparative analyses, and network-based drug combination testing.

Main Results:

• Resistance to Hsp90β inhibition involved significant rewiring of Rho GTPase signaling, cytoskeletal dynamics, and metabolic pathways, including mitochondrial dysfunction and redox imbalance.
• Aryl hydrocarbon receptor (AHR) activation and compensatory Hsp90α expression were linked to resistance phenotypes, with increased kynurenine levels observed.
• Gene-drug network analysis revealed collateral sensitivity to carboplatin, demonstrating synergy with Hsp90β inhibition in resistant models.

Conclusions:

• This study elucidates the molecular basis of resistance to Hsp90β-selective inhibitors, highlighting adaptive programs and identifying therapeutic vulnerabilities.
• The findings provide a systems-level framework for predicting Hsp90β inhibitor response and support rational combination strategies, such as carboplatin co-treatment, for preclinical development.