HSP90 inhibitors and cancer: Prospects for use in targeted therapies (Review)

Abstract

Heat shock protein 90 (HSP90) is a vital chaperone protein, regulating signaling pathways and correcting misfolded proteins in cancer cells by interacting with oncogenic client proteins and co‑chaperones. The inhibition of HSP90 chaperone machinery has been demonstrated as a potential approach with which to inhibit tumor survival, proliferation, invasion and migration. Numerous HSP90 inhibitors have been reported and have exhibited value as cancer‑targeted therapies by interrupting the ATPase activity of HSP90, thus suppressing the oncogenic pathways in cancer cells. These inhibitors have been classified into three categories: i) N‑terminal domain (NTD) inhibitors; ii) C‑terminal domain (CTD) inhibitors; and iii) isoform‑selective inhibitors. However, none of these HSP90 inhibitors are used as clinical treatments. The major limiting factors can be summarized into drug resistance, dose‑limiting toxicity and poor pharmacokinetic profiles. Novel HSP90‑targeted compounds are constantly being discovered and tested for their antitumor efficacy in preclinical and clinical trials, highlighting the prospect of the use of HSP90 inhibitors as cancer‑targeted therapies. Additionally, improved antitumor effects have been observed when HSP90 inhibitors are used in combination with chemotherapy, targeted agents, or immunotherapy. In the present review, the effects of HSP90 inhibitors on the management of the cancer process are discussed and previous and novel HSP90‑based therapeutic strategies in cancer treatment are summarized. Furthermore, prospective HSP90‑targeting candidates are proposed for their future evaluation as cancer treatments.

Keywords: HSP90 inhibitors; combination therapies; heat shock protein 90; selective inhibitors; targeted therapies.

Figure 1.

Cycling between the open conformation and closed conformation. HSP90 is predominantly an open V-shaped conformation with N-terminus separating. In open conformation, the binding sites on N-terminus are available to client proteins. ATP binds to specific sites in the NTD and induces the N-terminus to attach to the corresponding domain of the other homo-dimer, leading to the V-shaped conformation closed. Then N-domains are dimerized and associated with the M-domains, forming a twisted and compacted conformation. Following ATP hydrolysis to ADP and Pi is released from the binding pocket, the N-domains dissociate and HSP90 returns to its original open conformation. HSP90, heat shock protein 90; NTD, N-terminal domain; MD, middle domain; CTD, C-terminal domain.

Figure 2.

HSP90 is involved in establishing acquired capabilities of cancer cells. In cancer cells, HSF1 is released in response to cellular stress and subsequently upregulates the expression of HSP90. HSP90-client interactions triggers tumor-promoting signaling pathways which play essential roles in cancer cells. HSP90 inhibitors can suppresses all the signaling pathways concomitantly and interrupt the functions of HSP90 in cancer cells. HSP90, heat shock protein 90; HSF1, heat shock factor 1.