The rare capacity for
heat shock protein 90 (Hsp90) chaperones to support almost the entire cellular signaling network was viewed as a potential breakthrough to combat
tumor resistance to single-oncogene-based
therapeutics. Over 2 decades, several generations of Hsp90
ATP binding inhibitors have entered numerous
cancer clinical trials, but few have advanced to FDA approval for treatment of human
cancers. Herein, we report that Hsp90 expression varies dramatically, especially among different types of noncancer cells and organs. The highly variable levels of Hsp90, from as low as 1.7% to as high as 9% of their total cellular
proteins, were responsible for either an extreme sensitivity or an extreme resistance to a classical Hsp90
ATP-binding inhibitor. Among randomly selected
cancer cell lines, the same client
proteins for regulation of cell growth exhibited unexpectedly heterogenous reactions in response to an Hsp90
ATP-binding inhibitor, inconsistent with the current understanding. Finally, a minimum amount (<10%) of Hsp90β was still required for client protein stability and cell survival even in the presence of full Hsp90α. These new findings of Hsp90 expression in host and
isoform compensation in
tumor cells could complicate
biomarker selection, toxicity readout, and clinical efficacy of Hsp90-ATP-binding inhibitors in
cancer clinical trials.