Protein buildup mechanism shapes response to PROTAC drugs

The way cancer-causing proteins accumulate in tumors may influence how effectively a promising new generation of medicines can remove them, a study suggests. 

Researchers found that PROTAC (Proteolysis Targeting Chimeras) drugs were more effective at removing proteins that build up because they are not broken down properly than proteins that cancer cells continually produce in large amounts. 

Experts say the findings could help identify which tumors are most likely to respond to these therapies, supporting the development of more personalized cancer treatments. 

PROTACs are a new class of medicines that destroy harmful proteins by harnessing the cell's natural waste-disposal system. Unlike conventional drugs, which typically block the activity of disease-causing proteins, PROTACs are designed to remove them altogether. 

Many cancers depend on high levels of proteins that drive uncontrolled cell growth. These proteins can accumulate either because they are not broken down properly or because cancer cells produce them in excess, but it was unclear whether this affects how well PROTACs work. 

Researchers from the University of Edinburgh used β-catenin, a protein involved in many cancers, to investigate this question. 

The team developed methods to make β-catenin either harder for cells to break down or quicker for cells to produce. They then tested how effectively a PROTAC could remove it. 

The results revealed a clear difference between the two mechanisms. When β-catenin accumulated because it was not being broken down properly, the PROTAC was able to reduce protein levels to a similar minimum level regardless of how much had built up. 

However, when cells were producing β-catenin at a higher rate, protein levels remained elevated after treatment because new protein continued to be made. 

Researchers say the findings suggest that the success of PROTAC therapies may depend not only on how much of a cancer-driving protein is present, but also on why it has accumulated in the first place. 

By improving understanding of how tumor genetics shapes responses to targeted protein degradation, this study could help researchers identify which patients are most likely to benefit from these therapies and support the development of more personalized approaches to cancer treatment." 

Andrew Wood, Principal Investigator, University of Edinburgh's Institute of Genetics and Cancer

Professor Matthew Walters, Chair of Medical Research Scotland, said: "Medical Research Scotland is proud to have supported this important study, which we hope will help in the development of more targeted therapies for cancer. This research reflects our commitment to backing high-quality work with the potential to improve lives in Scotland and beyond."