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Leveraging a novel protein tagging strategy offers new route to cancer treatment

In a pioneering collaboration with AbbVie, Northwestern researchers have discovered a new way to potentially treat cancer by targeting and removing harmful proteins from cells.

An emerging approach in medicine and research, called "targeted protein degradation" (TPD), works by using special compounds to help the cell's natural machinery destroy proteins that cause diseases like cancer.

TPD uses small molecules or biologic drugs to tag unwanted proteins for removal in tumor cells. Special compounds act like matchmakers, bringing the unwanted protein close to the natural protein-disposal system in the cell.

One type of tagging molecule, called PROTACs, has two ends—one end binds to the target protein and the other connects to a disposal enzyme called an E3 ligase. Once attached, the E3 ligase tags the unwanted protein with a molecular "trash signal," telling the cell to break it down.

The study, in the Journal of the American Chemical Society, found that a specific cancer-related mutation in an E3 ligase, called FBXW7-R465C, can be used to help destroy tumor-promoting proteins in cancer cells.

By creating a special compound that binds FBXW7-R465C, the Northwestern team was able to direct this mutant protein to accelerate degradation of other tumor-promoting proteins. Only the mutated cancer cells, which have the faulty FBXW7 protein, are affected, leaving healthy cells unharmed. This selectivity dramatically reduces the potential for toxic side effects.

"Targeting specific mutant proteins, such as KRAS-G12C, has been a successful approach in many areas of medicine," says Xiaoyu Zhang, Assistant Professor of Chemistry and the study's corresponding author. "However, this strategy has not yet been applied in the TPD field to target a mutant E3 ligase for protein degradation.

"Our study shows that FBXW7-R465C mutant can be targeted by bifunctional small molecules to break down harmful proteins."

Zhang is a member of the Chemistry of Life Processes Institute (CLP). The Institute is at the forefront of the study of human proteins and their impact on human health and disease.

"The mutant targeted in this study is extremely common in cancer but was thought to have no function for some time. Our work excitingly suggests that it not only retains function but can be harnessed for therapeutic benefit," says Ananya Basu, first author of the study and a graduate student in Zhang's lab. Basu is a current University Presidential Fellow and a former member of CLP's Predoctoral Training Program.

The research was conducted in partnership with AbbVie. Zhang's lab demonstrated the potential of the FBXW7-R465C mutation for TPD applications, while the AbbVie team applied its biochemical expertise to provide critical evidence supporting its role in TPD.

"By designing molecules that take advantage of this mutation, we were able to selectively degrade target proteins in cancer cells carrying this mutation. This approach could be a game changer in developing cancer-specific therapies that can target diseased cells while sparing healthy ones," says Basu.