Targeting HSP90 as a Novel Therapy for Cancer: Mechanistic Insights and Translational Relevance

Abstract

Heat shock protein (HSP90), a highly conserved molecular chaperon, is indispensable for the maturation of newly synthesized poly-peptides and provides a shelter for the turnover of misfolded or denatured proteins. In cancers, the client proteins of HSP90 extend to the entire process of oncogenesis that are associated with all hallmarks of cancer. Accumulating evidence has demonstrated that the client proteins are guided for proteasomal degradation when their complexes with HSP90 are disrupted. Accordingly, HSP90 and its co-chaperones have emerged as viable targets for the development of cancer therapeutics. Consequently, a number of natural products and their analogs targeting HSP90 have been identified. They have shown a strong inhibitory effect on various cancer types through different mechanisms. The inhibitors act by directly binding to either HSP90 or its co-chaperones/client proteins. Several HSP90 inhibitors-such as geldanamycin and its derivatives, gamitrinib and shepherdin-are under clinical evaluation with promising results. Here, we review the subcellular localization of HSP90, its corresponding mechanism of action in the malignant phenotypes, and the recent progress on the development of HSP90 inhibitors. Hopefully, this comprehensive review will shed light on the translational potential of HSP90 inhibitors as novel cancer therapeutics.

Keywords: INHIBITORS; cancer therapeutics; heat shock protein 90; translational relevance.

Figure 1

Co-chaperones of HSP90 and its function. HSP90 comprises four isoforms: (1) HSP90α (an inducible form) and HSP90β (a constitutive form) are mainly located in the cellular cytosol; (2) the glucose-regulated protein (GRP94) is localized in the endoplasmic reticulum; (3) Hsp75/tumor necrosis factor receptor associated protein 1 (TRAP-1, also known as mitochondrial HSP90) is located on the mitochondria [7,8]. All HSP90 isoforms play critical roles in cancer, neurodegenerative disorders, and other disease states, indicating that their pharmacological targeting may have profound implications for the treatment of these illnesses [9].

Figure 2

Number of HSP90 inhibitors used in different cancer types under clinical evaluation (only recruited/active/completed were counted).