This analysis uncovers how signaling pathways influence the sensitivity of degrader responses in cell contexts, suggesting new therapeutic insights.
Key Points
Investigate the impact of cell context on targeted protein degradation sensitivity, particularly focusing on the role of EGFR signaling in STAT3 degradation.
Developed luminescent immunoassays on the Lumit platform for measuring degrader potency and selectivity.
Tested multiple target-degrader pairs including BRD4-ARV-771 and STAT3-SD-36 across various cell lines.
Analyzed potential causes of potency shifts in A431 cells compared to others.
Examined differences in membrane permeability, ubiquitination, and expression levels of STAT3 and EGFR.
A431 cells showed a potency shift for STAT3 degrader SD-36 with DC50 values in the µM range, unlike other cell lines with nM range.
Higher EGFR expression in A431 cells correlated with decreased efficacy of the degrader.
Decreasing EGFR levels or inhibiting its phosphorylation restored SD-36 potency.
Identified PARylation and PERK pathways as additional factors influencing STAT3 degradation in specific cell contexts.