The current status and future prospects for therapeutic targeting of KEAP1-NRF2 and β-TrCP-NRF2 interactions in cancer chemoresistance.

Drug resistance is one of the biggest challenges in cancer treatment and limits the potential to cure patients. In many tumors, sustained activation of the protein NRF2 makes tumor cells resistant to chemo- and radiotherapy. Thus, blocking inappropriate NRF2 activity in cancers has been shown to reduce resistance in models of the disease. There is a growing scientific interest in NRF2 inhibitors. However, the compounds developed so far are not target-specific and are associated with a high degree of toxicity, hampering clinical applications. Compounds that can enhance the binding of NRF2 to its ubiquitination-facilitating regulator proteins, either KEAP1 or β-TrCP, have the potential to increase NRF2 degradation and may be of value as potential chemosensitising agents in cancer treatment. Approaches based on molecular glue-type mechanisms, in which ligands stabilise a ternary complex between a protein and its binding partner have shown to enhance β-catenin degradation by stabilising its interaction with β-TrCP. This strategy could be applied to rationally discover degradative β-TrCP-NRF2 and KEAP1-NRF2 protein-protein interaction enhancers. We are proposing a novel approach to selectively suppress NRF2 activity in tumors. It is based on recent methodology and has the potential to be a promising new addition to the arsenal of anticancer agents.