In lab, protein buildup may shape PROTAC cancer response

In laboratory experiments at the University of Edinburgh, researchers changed how cancer-linked β-catenin accumulated inside cells, then tested a PROTAC drug against it. The result was a split: the drug removed the protein more effectively when cells failed to break it down than when they were producing it at a higher rate.

PROTACs — short for Proteolysis Targeting Chimeras — work by recruiting a cell’s natural waste-disposal system to destroy a harmful protein. That differs from conventional medicines, which typically block the activity of a disease-driving protein without removing it.

The team found that impaired breakdown did not prevent the PROTAC from pushing β-catenin down to a similar minimum level, even when more protein had accumulated. But when cells continually made β-catenin in larger amounts, protein levels remained elevated after treatment because fresh molecules kept arriving.

So what does this change, concretely? For cancer researchers developing PROTAC therapies, measuring why a tumor has accumulated a target protein could become part of deciding which tumors are most likely to respond. That could support more personalized treatment strategies, although the study does not establish a patient-selection test or clinical benefit.

Andrew Wood, principal investigator at the University of Edinburgh’s Institute of Genetics and Cancer, said the work could improve understanding of how tumor genetics shapes responses to targeted protein degradation. The evidence currently comes from laboratory tests using β-catenin; the findings still need to inform research beyond this experimental setting.