Overcoming Resistance in EGFR‐Mutant Cancers: A Comprehensive Review of Inhibitor Evolution and SAR‐Based Design

The epidermal growth factor receptor (EGFR) is a key target in cancer therapy, mainly in non-small cell lung cancer (NSCLC). Though, the efficacy of EGFR-targeted therapies is limited by the development of resistance. This comprehensive review details the structural biology of EGFR and its role in oncogenic signaling, elucidating the major activating mutations, particularly exon 19 deletions and L858R point mutations, and acquired resistance. The progressive development of EGFR tyrosine kinase inhibitors (TKIs), from first-generation ATP-competitive inhibitors (e.g., gefitinib, erlotinib) to third-generation covalent agents (e.g., osimertinib) and emerging fourth-generation allosteric and degradation approaches, are critically examined for their mechanisms, efficacy, and clinical limitations. We have also discussed about the intrinsic and acquired resistance mechanisms, including alternative oncogenic drivers (KRAS, ALK), bypass pathway activations (MET, HER2), and phenotypic changes like epithelial-mesenchymal transition. Additionally, we emphasize the role of computational modeling, high-throughput SAR studies, and preclinical models, including patient-derived xenografts and organoids, in guiding rational drug design. Emerging approaches integrating artificial intelligence, machine learning, and precision oncology hold potential to accelerate EGFR-targeted drug discovery. The combination strategies with immunotherapy, and anti-angiogenic agents are considered in the context of improving patient outcomes. Together, ongoing advances in understanding EGFR signaling and resistance mechanisms are driving the development of next-generation inhibitors and personalized therapies, with the ultimate goal of overcoming drug resistance and improve patient outcomes in EGFR-mutant cancers.