Targeted Protein Degradation Strategies for Lung Cancers: Focusing on Epidermal Growth Factor Receptor

ABSTRACT Lung cancer remains the leading cause of cancer‐related mortality worldwide, with dysregulation of epidermal growth factor receptor (EGFR) playing a pivotal role in its pathogenesis and progression. Although EGFR‐targeted tyrosine kinase inhibitors (TKIs) initially provide clinical benefits, resistance inevitably develops. Targeted protein degradation (TPD) offers a paradigm shift in cancer therapy by eliminating pathogenic proteins entirely, rather than merely inhibiting their function. This review comprehensively examines TPD strategies for lung cancer treatment, focusing on EGFR as an exemplary target. We trace the evolution of proteolysis targeting chimeras (PROTACs) from first‐generation compounds to sophisticated degraders with enhanced selectivity and potency. Structural insights from AlphaFold3 predictions reveal critical EGFR features that guide rational degrader design. We systematically compare EGFR‐targeting PROTACs, evaluating their degradation kinetics, mutant selectivity, and clinical potential. Beyond traditional small‐molecule PROTACs, we explore emerging modalities—including peptide‐based, antibody‐based, and nucleic acid‐based degraders—each offering unique advantages for overcoming current therapeutic limitations. We also discuss alternative TPD strategies, namely, molecular glues and lysosome‐targeting chimeras (LYTACs), which expand the therapeutic arsenal against EGFR. Importantly, we identify resistance mechanisms specific to protein degraders: E3 ligase loss or mutation, EGFR alterations that disrupt ternary complex formation, deubiquitinase upregulation, and degradation pathway dysfunction. By integrating structural biology, medicinal chemistry, and clinical insights, this review provides a comprehensive roadmap for developing next‐generation EGFR degraders capable of overcoming resistance and improving outcomes for lung cancer patients.