Targeting Hsp90 in Cancer for 25 Years: Failure of Previous Clinical Trials and New Hope for Future Therapeutics

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hsp90 ATP-binding inhibitors in clinical trials have not fully disclosed their mechanism of action (MOA).
• An "extra effect" of Hsp90 inhibitors, ignored since 2004, involves membrane-impermeable compounds inhibiting tumor cell invasion and metastasis.
• Structurally identical inhibitors demonstrate distinct activities based on membrane permeability, suggesting dual targeting.

Purpose of the Study:

• To re-evaluate the MOA of Hsp90 ATP-binding inhibitors in cancer therapy.
• To investigate the contribution of intracellular and extracellular Hsp90 inhibition to clinical trial outcomes.
• To identify the specific inhibitory function responsible for observed toxicity and limited efficacy in Hsp90 inhibitor trials.

Main Methods:

• Analysis of existing clinical trial data for Hsp90 ATP-binding inhibitors.
• Comparison of effects between membrane-permeable and membrane-impermeable Hsp90 inhibitors.
• In vitro and in vivo studies on tumor cell invasion and metastasis.

Main Results:

• Clinical trial outcomes of Hsp90 inhibitors are a combined effect of targeting intracellular Hsp90 chaperone and extracellular Hsp90 (eHsp90) non-chaperone functions.
• Membrane-impermeable inhibitors show significant inhibition of tumor cell invasion and metastasis.
• The dual inhibition mechanism may explain the toxicity and limited efficacy observed in numerous clinical trials.

Conclusions:

• The dual targeting of intracellular and extracellular Hsp90 by ATP-binding inhibitors is a critical factor in their therapeutic effects and toxicities.
• Clarifying the specific roles of intracellular and extracellular Hsp90 inhibition is essential for future drug design.
• Addressing this dual MOA could lead to a paradigm shift in developing next-generation Hsp90-targeted cancer therapeutics.