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

All previous IND (investigational new drug) applications to US FDA for launching clinical trials with Hsp90 ATP-binding inhibitors only provided a partial, if not misleading, account of the inhibitors' actual MOA (mechanism of action). Since 2004, studies have repeatedly shown a previously unanticipated "extra effect" of these inhibitors, but it has been incomprehensively ignored by the Hsp90 community. Membrane-impermeable, otherwise structurally identical, ATP-binding Hsp90 inhibitors show robust inhibition of tumor cell invasion in vitro and metastasis in vivo. Based on this new finding, the reported outcomes of around 90 monotherapy clinical trials with Hsp90 ATP-binding inhibitors since 1999 were actually a combined effect of targeting both intracellular Hsp90 chaperone and extracellular Hsp90 (eHsp90) non-chaperone functions by the inhibitors. A critical unanswered question remains: which form of the dual inhibitions caused the observed toxicity in humans that led to the spectacular failure of the trials and which underlies the limited efficacy that might be the real reason for the only approval of the orally administered ATP-binding inhibitor, Pimitespib (TAS-116), in 2022 by Japan? We suggest that addressing this question could prompt a paradigm shift in the design of next-generation anti-Hsp90 cancer therapeutics.