HSP90 as a platform for the assembly of more effective cancer chemotherapy.

Since initial discovery of the first HSP90 inhibitor over a decade and a half ago, tremendous progress has been made in developing potent and selective compounds with which to target this chaperone in the treatment of cancers. These compounds have been invaluable in dissecting how HSP90 supports the dramatic alterations in cellular physiology that constitute the malignant phenotype and give rise to the clinical manifestations of diverse cancers. Unfortunately, single agent activity for HSP90 inhibitors has been disappointingly modest against recurrent, refractory cancers in most of the clinical trials that have been reported to date. This problem could be due to pharmacological limitations of the first-generation inhibitors that have been most extensively studied. But we suggest it may well be intrinsic to the target itself. This review will focus on how the utilization of HSP90 by cancer cells might be targeted to enhance the activity of other anticancer drugs while at the same time limiting the ability of advanced cancers to adapt and evolve drug resistance; the net result being more durable disease control. A better understanding of these fundamental issues will surely make the ongoing clinical development of HSP90 inhibitors as anticancer drugs less empiric, more efficient and hopefully more successful. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).