Targeting heat shock proteins in metastatic castration-resistant prostate cancer

Heat shock proteins (HSPs) are molecular chaperones that regulate protein homeostasis, signal transduction and transcriptional networks, and are key drivers of adaptive stress-response pathways in many malignanciesHSPs are highly expressed in many cancers, and subversion of their chaperone functions enables survival of malignant cells subjected to proteotoxic stressHSPs are important in androgen receptor function (including ligand binding and nuclear trafficking), and many HSP client proteins modulate key signalling and transductional networks in castration-resistant prostate cancer (CRPC) cellsExtensive preclinical data have demonstrated the utility of targeting HSPs, including HSP90, HSP70, HSP27 and clusterin, in prostate cancerClinical development of HSP blockade as a therapeutic strategy in CRPC has been challenging, but antisense oligonucleotides targeting HSP27 and clusterin have proceeded to late-stage clinical trialsIntegrating HSP blockade into the treatment paradigm for CRPC will require the development of potent, selective inhibitors of HSPs, and identification of rational combination strategies