Protein Degradation: Expanding the Toolbox to Restrain Cancer Drug Resistance

The review discusses the potential of protein degradation as a strategy to combat drug resistance in cancer treatment. It suggests that targeting the degradation process could be a more direct and faster strategy than intervening at the transcriptional level. The main systems responsible for protein or organelle degradation, proteasomal proteolysis and lysosomal proteolysis, are discussed. However, the routine application of inhibitors like bortezomib and chloroquine is still far off due to lack of precise targeting and side effects. The review emphasizes the need for further studies on protein degradation regulators like E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones to develop precise targeting strategies and reduce side effects. The review also discusses the role of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling. It concludes that understanding the molecular basis of how protein degradation regulates tumor drug resistance could help develop effective clinical strategies.