Protein accumulation in tumours may determine how well a new class of cancer drugs works, according to a study from the University of Edinburgh. Researchers found that PROTACs remove proteins more effectively when those proteins build up because the cell cannot break them down, rather than when cancer cells continually produce them in large amounts.
How the drugs function
PROTACs represent a distinct approach to treating cancer. Unlike conventional medicines that simply block the activity of disease-causing proteins, these drugs are designed to eliminate the proteins entirely by using the cell’s natural waste-disposal system. Many cancers rely on high levels of specific proteins to drive uncontrolled cell growth, but it was unclear whether the way these proteins accumulate affects drug efficacy.
The team investigated this by focusing on β-catenin, a protein involved in many types of cancer. They developed methods to make β-catenin harder for cells to break down or quicker for cells to produce. Testing how well a PROTAC could remove the protein 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 raised after treatment because new protein continued to be made.
Implications for treatment
The findings suggest that the success of PROTAC therapies depends not only on how much of a cancer-driving protein is present, but also on the reason for its accumulation. By improving understanding of how tumour genetics shapes responses to targeted protein degradation, the study could help researchers identify which patients are most likely to benefit from these therapies.
Andrew Wood, Principal Investigator at the University of Edinburgh’s Institute of Genetics and Cancer, said: “By improving understanding of how tumour 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 personalised approaches to cancer treatment.”
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.”
