Heterogeneous Responses and Isoform Compensation Dim the Therapeutic Window of Hsp90 ATP-Binding Inhibitors in Cancer
- 1 February 2022
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 42 (2), e0045921
- https://doi.org/10.1128/mcb.00459-21
Abstract
The rare capacity for heat shock protein-90 (Hsp90) chaperones to support almost the entire cellular signaling networks was viewed as a potential breakthrough point to combat tumor resistance to single oncogene-based therapeutics. Over two 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 dramatically vary especially among different types of non-cancer 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 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.Keywords
Funding Information
- h Programs
- DOD | US Army | Medical Command | Congressionally Directed Medical Research Programs (W81XWH-1810558)
- HHS | NIH | OSC | Common Fund (GM067100)
This publication has 36 references indexed in Scilit:
- Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancersBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2012
- A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumorsMolecular Biology of the Cell, 2012
- Hsp90 Molecular Chaperone Inhibitors: Are We There Yet?Clinical Cancer Research, 2012
- Heat shock protein 90 (HSP90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cellsProceedings of the National Academy of Sciences of the United States of America, 2011
- The Molecular Chaperone Hsp90α Is Required for Meiotic Progression of Spermatocytes beyond Pachytene in the MousePLOS ONE, 2010
- Targeting the dynamic HSP90 complex in cancerNature Reviews Cancer, 2010
- Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growthMolecular Carcinogenesis, 2006
- Identification of Potent Water Soluble Purine-Scaffold Inhibitors of the Heat Shock Protein 90Journal of Medicinal Chemistry, 2005
- Hsp90: the vulnerable chaperoneDrug Discovery Today, 2004
- A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitorsNature, 2003