Maximizing the Therapeutic Potential of HSP90 Inhibitors

Abstract

HSP90 is required for maintaining the stability and activity of a diverse group of client proteins, including protein kinases, transcription factors, and steroid hormone receptors involved in cell signaling, proliferation, survival, oncogenesis, and cancer progression. Inhibition of HSP90 alters the HSP90-client protein complex, leading to reduced activity, misfolding, ubiquitination, and, ultimately, proteasomal degradation of client proteins. HSP90 inhibitors have demonstrated significant antitumor activity in a wide variety of preclinical models, with evidence of selectivity for cancer versus normal cells. In the clinic, however, the efficacy of this class of therapeutic agents has been relatively limited to date, with promising responses mainly observed in breast and lung cancer, but no major activity seen in other tumor types. In addition, adverse events and some significant toxicities have been documented. Key to improving these clinical outcomes is a better understanding of the cellular consequences of inhibiting HSP90 that may underlie treatment response or resistance. This review considers the recent progress that has been made in the study of HSP90 and its inhibitors and highlights new opportunities to maximize their therapeutic potential.

Figure 1. The chaperone cycle of Hsp90 and effects of Hsp90 inhibition

As new client proteins are synthesized they are rapidly bound by Hsp40, independent of ATP and other proteins. Hsp40 then associates with Hsp70, stimulating ATPase activity and allowing Hsp70 to bind the client, thus forming the Hsp70-Hsp40 chaperone complex. Certain client proteins, such as transcription factors, are delivered to the ADP-bound ‘open’ form of Hsp90 by the Hsp70-Hsp40 chaperone complex via the TPR-containing co-chaperone Hsp70-Hsp90 Organizing Protein (HOP). The role of HOP in this complex is to reversibly link Hsp70 to Hsp90 through the MEEVD peptide to allow transfer of client proteins to Hsp90. Client binding leads to conformational changes within Hsp90 causing it to conform to an ATP-bound ‘closed’ state in association with the co-chaperone, p23. p23 preferentially binds the ATP-bound state of Hsp90 and stimulates dissociation of the Hsp70-Hsp40 complex from Hsp90. Kinases are delivered to Hsp90 through an alternative method that involves a complex with the co-chaperone Cell-Division Cycle 37 homologue (Cdc37). Cdc37 delivers client kinases via interactions with the ATP lid of Hsp90’s N-terminal domain and the highly conserved glycine-rich loop of the protein kinases N-lobe. These and other co-chaperone interactions induce conformational changes in client proteins that allow their maturation and activation. For all clients, the cycle ends with Hsp90 binding the co-chaperone Activator of Hsp90 ATPase 1 (Aha1), which causes stimulation of ATP hydrolysis by Hsp90, leading to release of the mature and active client protein. Inhibition of Hsp90 by small-molecule inhibitors acting at the N-terminal nucleotide site blocks ATP binding and hydrolysis, leading to arrest of the chaperone cycle, loss of co-chaperones from the chaperone complex, inhibition of client activity and ubiquitin-dependent proteasomal dependent degradation of the client.