title: The expanding proteome of the molecular chaperone HSP90.
abstract: The molecular chaperone HSP90 maintains the activity and stability of a diverse set of "client" proteins that play key roles in normal and disease biology. Around 20 HSP90 inhibitors that deplete the oncogenic clientele have entered clinical trials for cancer. However, the full extent of the HSP90-dependent proteome, which encompasses not only clients but also proteins modulated by downstream transcriptional responses, is still incompletely characterized and poorly understood. Earlier large-scale efforts to define the HSP90 proteome have been valuable but are incomplete because of limited technical sensitivity. Here we discuss previous large-scale surveys of proteome perturbations induced by HSP90 inhibitors in light of a significant new study using state-of-the-art SILAC technology combined with more sensitive high-resolution mass spectrometry (MS) that extends the catalog of proteomic changes in inhibitor-treated cancer cells. Among wide-ranging changes, major functional responses include downregulation of protein kinase activity and the DNA damage response alongside upregulation of the protein degradation machinery. Despite this improved proteomic coverage, there was surprisingly little overlap with previous studies. This may be due in part to technical issues but is likely also due to the variability of the HSP90 proteome with the inhibitor conditions used, the cancer cell type and the genetic status of client proteins. We suggest future proteomic studies to address these factors, to help distinguish client protein components from indirect transcriptional components and to address other key questions in fundamental and translational HSP90 research. Such studies should also reveal new biomarkers for patient selection and novel targets for therapeutic intervention.
authors.affiliation: Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Samant
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004260:DNA Repair; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020543:Proteome
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D020543:Proteome