Molecular Pathways: Targeting Hsp90—Who Benefits and Who Does Not

Abstract

Many kinases and hormone receptors, important for cancer cell proliferation and survival, bind to and are dependent on the Hsp90 cycle for their folding and maturation. This provides the rationale for the development of small-molecule ATP competitors that, inhibiting Hsp90 function, lead to degradation of the "client" proteins. After continual efforts to improve the pharmacologic properties and the tolerability of these molecules, several Hsp90 inhibitors have exhibited activity in both preclinical models and in the clinical setting. As is the case with many other targeted agents, patient selection seems to be the major limitation to the success of these compounds. ERBB2-positive patients with breast cancer are exquisitely sensitive to Hsp90 inhibition. This is because ERBB2 is indispensable for growth and survival of this subtype of cancer, and at the same time ERBB2 is a client protein strictly dependent on Hsp90 for its maturation and stability. Extensive preclinical work identifying other ERBB-like client proteins will likely lead to the ability to enhance selection of appropriate patients for enrollment in more rational clinical trials. Hsp90 inhibition has also been reported to synergize with other therapeutic agents. Several ongoing studies testing different combinations of Hsp90 inhibitors with other targeted agents will confirm whether Hsp90 inhibition can potentiate the efficacy of targeted therapy and/or prevent the emergence of drug resistance.

Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin*

“…As previously reported, inhibition of HSP90 expression can lead to depression of some signaling pathways involved in cancer progression and cell growth, including the MAPK/ERK cascade (61,63,64). Notably, our temporal profile of phosphorylation revealed that phosphorylated MAPK1 Thr 185 / Tyr 187 , a conserved TEY activation motif (62), was downregulated under slower response times (Fig.…”

“…We also noticed that one adhesion molecule expressed on the cell surface, Down syndrome cell adhesion molecule (DSCAM), behaved as an upstream regulator for other molecules associated with protein folding, including hsc70-interacting protein (ST13), EP300, and HSP90AB1. Moreover, the phosphorylation of HSP90AB1, a controller for chaperone complexes and cell signaling (52,61), could activate a downstream component of the MAPK/extracellular signal-regulated kinase (ERK) pathway, MAPK1 (62). MAPK/ERK signaling is known for its role in cell growth by regulating cell cycle, cell death and protein folding responses (62).…”

“…5B and 5C), implying the regulatory importance of site-specific phosphorylation of HSP90AB1. Although phosphosite Ser 255 has been identified in a previous study (36), the influence of HSP90 on signal transductions was only investigated at the total protein level (61,63). No evidence regarding the effects of HSP90 phosphorylation on MAPK activation has been reported (65).…”

Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy

“…This concept has been evaluated in many cancers [9][10][11][12][13][14][15][16], including numerous attempts in pre-clinical and clinical breast cancer models [17][18][19][20][21][22][23][24][25][26][27] (reviewed in [28]). …”

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

“…Though HSP90 inhibitors have been shown in different preclinical models to exert their potent antitumor activities by destabilizing HSP90 clients (9-13), they have also been shown to have limited single-agent activity in the clinical setting (3,8,14). One explanation for this discrepancy may be that the levels of drug exposure reached in patients are insufficient to effectively inhibit tumor cell HSP90 because of undesirable offtarget and/or HSP90-related adverse events.…”