Heat-shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of a growing number of signalling proteins that have been implicated in cancer cell survival, including several mutated proteins that are only found in specific cancers. Furthermore, a growing body of evidence suggests that cancer cells are particularly dependent on Hsp90 for their growth and survival, and, therefore, are more sensitive to the effects of its inhibition than are non-transformed cells and tissues. Several chemically distinct Hsp90 inhibitors have shown encouraging antitumour activity in multiple preclinical model systems, and one Hsp90 inhibitor, the benzoquinone ansamycin 17-allylamino, 17-demethoxygeldanamycin, has completed five Phase I clinical trials, with a number of Phase II trials soon to be underway or in progress. Other Hsp90 inhibitors are either in Phase I clinical trial or under development. This update will focus on how the latest developments in Hsp90 biology may better inform the clinical development of Hsp90 inhibitors.

Heat-shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and overexpressed signalling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2) and hypoxia inducible factor-1alpha (HIF-1alpha). Through specific interaction with a single molecular target, Hsp90 inhibitors cause the destabilisation and eventual degradation of Hsp90 client proteins, and they have shown promising antitumour activity in preclinical model systems. One Hsp90 inhibitor, 17-allylamino-geldanamycin (17-AAG), is currently in Phase I clinical trials. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signalling pathways on which cancer cells depend for growth and survival. Further, because of the unique effect that Hsp90 inhibition has on cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent.