HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer

Area of Science:

• Oncology
• Molecular Biology
• Proteomics

Background:

• Acquired resistance to platinum (Pt)-based therapies presents a significant challenge in epithelial ovarian cancer (EOC) management.
• Identifying novel therapeutic targets is crucial for overcoming this resistance.

Purpose of the Study:

• To investigate the molecular mechanisms underlying acquired platinum resistance in EOC.
• To evaluate heat-shock protein 90 (HSP90) as a potential therapeutic target in platinum-resistant EOC.

Main Methods:

• Unbiased proteomics analysis of isogenic EOC models with acquired Pt resistance.
• Genetic knockout of heat-shock protein 90 alpha isoform.
• Pharmacological inhibition of HSP90 using 17-allylamino-17-demethoxygeldanamycin (17AAG) and ganetespib.
• Assessment of drug synergy, apoptosis, and DNA damage.
• Ex vivo and in vivo validation in patient-derived cultures and xenograft models.

Main Results:

• Proteomics identified HSP90 as a central hub in platinum-resistant EOC cells.
• HSP90 upregulation was observed in all resistant models.
• HSP90 inhibition, genetically or pharmacologically, resensitized resistant cells to cisplatin (CDDP).
• Combined treatment induced apoptosis and DNA damage, showing antitumor activity ex vivo and in vivo.

Conclusions:

• HSP90 is a key mediator of acquired platinum resistance in EOC.
• Combining platinum compounds with HSP90 inhibitors represents a promising strategy to overcome resistance.
• This approach warrants further clinical evaluation for platinum-resistant EOC patients.