A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors

• Published in: Nature 2003-09, Vol.425 (6956), p.407-410
• Main Authors: Burrows, Francis J, Kamal, Adeela, Thao, Lia, Sensintaffar, John, Zhang, Lin, Boehm, Marcus F, Fritz, Lawrence C
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - metabolism; Adenosine Triphosphate - metabolism; Antineoplastic agents; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Benzoquinones; Biological and medical sciences; Cell Line; Cysteine Endopeptidases - metabolism; General aspects; Heat; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - chemistry; HSP90 Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Humans; Inhibitors; Inhibitory Concentration 50; Lactams, Macrocyclic; letter; Medical sciences; Molecules; multidisciplinary; Multienzyme Complexes - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Precipitin Tests; Proteasome Endopeptidase Complex; Protein Binding - drug effects; Protein Conformation; Rifabutin - analogs & derivatives; Rifabutin - metabolism; Rifabutin - pharmacology; Science; Science (multidisciplinary); Substrate Specificity; Tumor Cells, Cultured; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature01913

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 p53. Hsp90 inhibitors bind to Hsp90, and induce the proteasomal degradation of Hsp90 client proteins. 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 trials. 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.