Targeting the dynamic HSP90 complex in cancer

Heat shock protein 90 (HSP90) is a molecular chaperone of numerous oncoproteins. Therefore, cancer cells can be considered to be 'addicted' to this molecule. HSP90 is also a mediator of cellular homeostasis. As such, it facilitates numerous transient low-affinity protein–protein interactions that have only recently been identified using bioinformatic and proteomic techniques. Although primarily a cytoplasmic protein, HSP90 affects diverse nuclear processes, including transcription, chromatin remodelling and DNA damage-induced mutation. HSP90 is a conformationally dynamic protein. ATP binding to the amino (N) domain and its subsequent hydrolysis by HSP90 drive a conformational cycle that is essential for chaperone activity. In eukaryotes, co-chaperones and post-translational modifications regulate both client interactions with HSP90 and HSP90 ATPase activity. Co-chaperones and post-translational modifications can also affect the efficacy of HSP90 inhibitors. HSP90 inhibitors currently under clinical evaluation interact with the N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cycle, leading to client protein degradation. Because of the HSP90 client repertoire, HSP90 inhibitors may combat oncogene switching, which is an important mechanism of tumour escape from tyrosine kinase inhibitors. Derivatives of the coumarin antibiotic novobiocin represent an alternative strategy for inhibiting HSP90 by targeting a unique carboxy-terminal (C) domain. Optimal development of HSP90-directed therapeutics will depend on synthesizing information gained from careful genetic analysis of primary and metastatic tumours with an understanding of the unique environmental context in which the tumour is thriving at the expense of the host.