Researchers provide insights on how to overcome resistance in cancer therapy

Traditional targeted cancer therapies mainly rely on drugs that bind pathogenic proteins and inhibit their function. The latest development of drugs has brought forward chemical molecules known as degraders, which force the targeted degradation of disease relevant proteins. This method of targeted protein degradation is not only more efficient, but also better at overcoming potential drug resistance. For many years, CeMM Principal Investigator Georg Winter and his research group have been working on further developing this paradigm. Small-molecule degraders work like a glue by recruiting the defective, disease-causing protein to effectors of the cellular waste disposal systems, which are known as E3 ubiquitin ligases. This binding in turn kick-starts the degradation process of the defective protein. Alexander Hanzl, first author and PhD student in the Winter Lab at CeMM, conducted a study to investigate which resistances can arise during the degradation process. He explains, "One challenge with degraders is that they have to bind two sites at once – both the defective protein and a protein of our cell's own degradation system, the E3 ligase. It is therefore all the more important to understand the process of binding and ubiquitination in functional detail. Only then can future degraders be modeled in the best possible way".