HSP90 and the chaperoning of cancer

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Abstract
Most heat-shock proteins (HSPs) are constitutively expressed molecular chaperones that guide the normal folding, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth and survival. Their levels of intracellular expression increase in response to protein-denaturing stressors, such as temperature change, as an evolutionarily conserved response to restore the normal protein-folding environment and to enhance cell survival. The essential chaperoning functions of HSPs are subverted during oncogenesis to make malignant transformation possible and to facilitate rapid somatic evolution. Functioning as biochemical buffers for the numerous genetic lesions that are present within tumours, chaperones, especially HSP90, allow mutant proteins to retain or even gain function while permitting cancer cells to tolerate the imbalanced signalling that such oncoproteins create. Highly specific inhibitors of HSP90 have been identified that redirect its chaperoning activity and decrease cellular levels of the many cancer-related client proteins that depend on it for their function. The use of HSP90 inhibitors has proven invaluable at a basic level in probing the complex cellular functions of this chaperone. The modulation of client protein levels has been demonstrated in animal models and cancer patients following systemically well-tolerated exposure to the HSP90 inhibitor 17AAG, which is the first in its class. Work is ongoing to identify and develop new HSP90 inhibitors with improved pharmacological properties. The best way to exploit the novel mechanism of action of HSP90 inhibitors for anticancer therapy remains to be defined, but probably involves combination with conventional cytotoxic drugs or other molecularly targeted agents.