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Updated: Jun 5, 2025
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Discovery of a molecular glue for EGFR degradation
Hairui Wang1,2, Hui Wang3, Rui Wang4
1Department of Breast Cancer, Third Affiliated Hospital, Kunming Medical University, Kunming, Yunnan, China.
Abstract:
Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.
Insights
A novel molecular glue, CDDO-Me, targets epidermal growth factor receptor (EGFR) for degradation in triple-negative breast cancer (TNBC). This approach shows potential for treating TNBC by reducing EGFR levels.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant epidermal growth factor receptor (EGFR) expression drives tumor pathogenesis.
- Targeting EGFR in triple-negative breast cancer (TNBC) presents significant pharmacological challenges.
- Molecular glue (MG) degraders offer a novel strategy for targeted protein removal.
Purpose of the Study:
- To identify and characterize a new molecular glue capable of degrading EGFR.
- To investigate the mechanism by which the molecular glue induces EGFR degradation.
- To evaluate the therapeutic potential of the molecular glue in preclinical models of TNBC.
Main Methods:
- Identification of a novel molecular glue, CDDO-Me.
- Investigation of the interaction between CDDO-Me, EGFR, and KEAP1 (E3-ubiquitin ligase adapter).
- Assessment of EGFR ubiquitination and degradation pathways (autophagy-dependent lysosomal pathway).
- Evaluation of CDDO-Me efficacy in cell-derived xenografts and patient-derived organoid models.
Main Results:
- CDDO-Me induced binding between EGFR and KEAP1, leading to EGFR ubiquitination and degradation.
- Degradation occurred via an autophagy-dependent lysosomal pathway, involving direct interaction with EGFR's tyrosine kinase domain.
- KEAP1 knockdown reduced EGFR degradation, confirming its role in the process.
- CDDO-Me attenuated TNBC progression in preclinical models by accelerating EGFR degradation.
Conclusions:
- CDDO-Me represents a novel molecular glue degrader targeting EGFR.
- The mechanism involves KEAP1-mediated ubiquitination and autophagy-dependent lysosomal degradation of EGFR.
- CDDO-Me demonstrates significant therapeutic potential for triple-negative breast cancer.
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