TARGETING HSP90 FUNCTION TO TREAT CANCER: MUCH MORE TO BE LEARNED

Molecular chaperones or so-called heat shock proteins act as central integrators of protein homeostasis within cells. Among the major chaperones, however, Hsp90 is unique because it is not required for the biogenesis of most polypeptides. Instead, it oversees a surprisingly diverse network of conformationally labile client substrates that regulate signaling pathways and gene expression. Many of the processes modulated by Hsp90 are dysregulated in cancer cells including cell cycle control, apoptosis and chromatin re-modeling. Over the past decade, much of the progress achieved in understanding the complex role of Hsp90 in cancer biology has been made possible by the discovery of several natural product antitumor antibiotics that selectively inhibit Hsp90 function. These compounds have the ability to accomplish what most molecularly targeted anticancer therapies do not –the simultaneous disruption of multiple processes critical to tumor cell growth and survival. Now, great enthusiasm exists over the prospect of targeting Hsp90 function to treat cancer. New chemotypes with improved pharmacology are being developed and clinical trials have demonstrated that Hsp90 function can be inhibited in cancer patients without undue acute toxicity. Remarkable progress has been made, but much more remains to be learned if we are to succeed in the challenge of defining safe and effective ways to exploit Hsp90 inhibition in the treatment of patients