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.
[1]Kunming Med Univ, Affiliated Hosp 3, Dept Breast Canc, Kunming, Yunnan, Peoples R China.
[2]Chinese Acad Sci, Kunming Inst Zool, Natl Key Lab Genet Evolut & Anim Models, Kunming, Yunnan, Peoples R China.
[3]Army Med Univ, Southwest Hosp, Dept Breast & Thyroid Surg, Chongqing, Peoples R China.
[4]China West Normal Univ, Nanchong, Sichuan, Peoples R China.
[5]Jianyang City Peoples Hosp, Chengdu, Sichuan, Peoples R China.
[6]Chinese Acad Sci, Kunming Inst Zool, KIZ CUHK Joint Lab Bioresources & Mol Res Common D, Kunming 650203, Yunnan, Peoples R China.
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