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.

In Vivo Conformational Dynamics of Hsp90 and Its Interactors

“…CTD inhibitors have been shown to interfere with Hsp90 dimerization(Allan et al, 2006), and our data indicates Novobiocin selectively inhibits HS90B dimerization, in agreement with its weaker dimerization potential compared to HS90A(Csermely et al, 1998; Sreedhar et al, 2004). On the other hand, treatment with the NTD inhibitors, 17-AAG and XL888 lead to increased levels of HS90A homodimer and the HS90A-B heterodimer while having no effect on the HS90B homodimer, reflecting the induced heat shock response observed with Hsp90 inhibitors(Butler et al, 2015). Overall these results demonstrate the potential of quantitative cross-linking to sample drug specific conformational effects on Hsp90 in cells.…”

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

“…Although preclinical reports have shown broad activity of HSP90 inhibitors across various tumor types, single agent activity of HSP90 inhibitors against most malignancies including gliomas has been modest likely due to insufficient target inhibition, short duration of action or toxicities (47). Unlike other HSP90 inhibitors, Onalespib has a favorable pharmacokinetic and pharmacodynamic profile exerting a prolonged inhibition of HSP90 resulting in a sustained reduction in levels of its client oncoproteins and their downstream targets (22).…”

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

“…Clinical activity of Hsp90 inhibitors has been demonstrated primarily in tumors with known alterations in oncoproteins which are Hsp90 client proteins, such as amplified HER2 in breast cancer, ALK rearrangements in non-small cell lung cancer and mutant BRAF in melanoma (Solit & Chiosis 2008;Butler et al 2015). Therefore, as with PARP inhibitors, it is likely that the major clinical impact will be obtained in stratified patient groups selected for known biomarkers indicating sensitivity to these agents.…”