Exploring Degradation of Mutant and Wild-Type Epidermal Growth Factor Receptors Induced by Proteolysis-Targeting Chimeras

selectively degraded the mutant but not the WT EGFR through both ubiquitination/proteasome and autophagy/lysosome pathways. Interestingly, we found that the mutant but not the WT EGFR can effectively form EGFR-PROTAC-E3 ligase ternary complexes. Furthermore, we found that PI3K inhibition sensitized WT EGFR to PROTAC-induced degradation and combination treatment with a PI3K inhibitor enhanced antiproliferation activities of EGFR degraders in cancer cells harboring WT EGFR, providing a potential therapeutic strategy for patients with WT EGFR overexpression.