Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models

Area of Science:

• Molecular Biology
• Structural Biology
• Cancer Research

Background:

• Heat shock protein 27 (HSP27) is crucial for cancer cell survival and oncogene addiction.
• HSP27 phosphorylation is a key regulatory step and a potential drug target.
• The disordered structure of HSP27 complicates traditional drug discovery methods.

Purpose of the Study:

• To elucidate the structural basis of HSP27 function and identify druggable sites.
• To investigate the potential of ivermectin as an inhibitor of HSP27 activity.
• To explore ivermectin's efficacy in combination therapy for cancer treatment.

Main Methods:

• Multistep biochemical, structural, and computational analyses were employed.
• Characterization of a 24-monomer HSP27 complex (12 dimers).
• In vitro and in vivo assays using cancer models.

Main Results:

• A novel spherical 24-monomer HSP27 complex with a defined phosphorylation pocket was identified.
• Ivermectin directly binds to this pocket, inhibiting MAPKAP2-mediated phosphorylation and depolymerization of HSP27.
• Ivermectin blocked HSP27-regulated survival signaling and client-oncoprotein interactions.
• Combination therapy with ivermectin enhanced the efficacy of anti-androgen receptor and anti-EGFR drugs in preclinical cancer models.

Conclusions:

• Ivermectin effectively inhibits HSP27 phosphorylation and downstream signaling.
• Targeting HSP27 with ivermectin represents a viable strategy to overcome resistance to oncogenic pathway inhibitors.
• Repurposing ivermectin offers a new approach for cotargeting stress-adaptive responses in cancer therapy.