Molecular crosstalk between the proteasome, aggresomes and autophagy: Translational potential and clinical implications

Targeting the ubiquitin+proteasome protein degradation pathway with the therapeutic agent bortezomib has significantly improved the survival of cancer patients but drug resistance inevitably develops. Aggresomes and the autophagy pathway serve as compensatory protein-clearance mechanisms that eradicate potentially toxic proteins to promote resistance to proteasome inhibitors and, hence, tumor survival. Pre-clinical evidence has emerged to demonstrate active crosstalk between these protein degradation pathways and has revealed novel therapeutic targets and strategies. Translational research and clinical trials are now focused on these pathways to prevent the emergence of drug resistance, enhance apoptosis and further improve the survival of cancer patients.

► Proteasome inhibitors are effective cancer therapeutics that improve patient survival. ► Resistance to proteasome inhibitors inevitably develops in patients to reduce clinical efficacy. ► Resistance may be mediated by autophagy to remove potentially toxic proteins that accumulate upon proteasome inhibition. ► Translational and clinical studies are focused to target autophagy and overcome drug resistance to proteasome inhibitors.