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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Existing epidermal growth factor receptor (EGFR) proteolysis-targeting chimeras (PROTACs) degrade mutant EGFR but not wild-type (WT) EGFR.
• The mechanism behind this selectivity remains unclear, limiting therapeutic applications.

Purpose of the Study:

• To discover novel EGFR degraders with enhanced selectivity.
• To elucidate the molecular mechanism of selective mutant EGFR degradation.
• To explore therapeutic strategies for WT EGFR-overexpressing cancers.

Main Methods:

• Structure-activity relationship studies to identify new EGFR degraders (Compounds 31 and 72).
• Mechanistic studies investigating degradation pathways (ubiquitination/proteasome and autophagy/lysosome).
• Analysis of ternary complex formation between EGFR, PROTAC, and E3 ligase.
• Inhibition of phosphoinositide 3-kinase (PI3K) to assess effects on WT EGFR degradation.

Main Results:

• Discovery of two novel EGFR degraders, 31 (MS9449) and 72 (MS9427), that selectively degrade mutant EGFR.
• Demonstration that both mutant and WT EGFR degrade via ubiquitination/proteasome and autophagy/lysosome pathways.
• Identification of preferential ternary complex formation between mutant EGFR, PROTACs, and E3 ligase.
• PI3K inhibition sensitizes WT EGFR to PROTAC degradation and enhances anti-proliferation activity in cancer cells.

Conclusions:

• Compounds 31 and 72 exhibit selective degradation of mutant EGFR.
• The formation of EGFR-PROTAC-E3 ligase ternary complexes is crucial for selectivity.
• Combining PI3K inhibitors with EGFR degraders presents a promising therapeutic strategy for WT EGFR-overexpressing cancers.