Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signalling proteins, including HER-2/ErbB2, Akt, Raf-1, Bcr-Abl and mutated p531,2,3,4,5,6,7. Hsp90 inhibitors bind to Hsp90, and induce the proteasomal degradation of Hsp90 client proteins6,8,9,10,11. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells compared to normal cells, and the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is currently in phase I clinical trials12,13. However, the molecular basis of the tumour selectivity of Hsp90 inhibitors is unknown. Here we report that Hsp90 derived from tumour cells has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells. Tumour Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. These results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics.
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We thank D. Toft for critical reading of the manuscript. We also thank G. Timony for preparing the scatter plots, P. Karjian for quantitative western blotting of Hop and p23, and other team members at Conforma Therapeutics Corporation for discussions and suggestions.
All authors are current or former employees and stock option holders of Conforma Therapeutics Corp.
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Kamal, A., Thao, L., Sensintaffar, J. et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–410 (2003). https://doi.org/10.1038/nature01913
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