Mechanism-Matched Pharmacology of Resistance in EGFR-Mutant NSCLC: Genomic Bypass, Lineage Plasticity, Antibody-Drug Conjugates, and Candidate Biophysical Targets

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) often responds to EGFR tyrosine kinase inhibitors but develops heterogeneous resistance. This structured narrative review integrates clinical and experimental evidence on resistance after osimertinib and intensified EGFR-directed therapy. It distinguishes on-target EGFR alterations, MET and ERBB-family bypass, downstream signaling, oncogenic fusions, histologic transformation, epithelial–mesenchymal plasticity, and drug-tolerant persistence, linking each mechanism to an appropriate assay and treatment context. We evaluate next-generation EGFR inhibitors, EGFR-MET combinations, bispecific antibodies, platinum-pemetrexed intensification, and antibody-drug conjugates directed at HER3, TROP2, or HER2. Clinical validation is assessed separately from mechanistic causality, with attention to allelic phase, central nervous system exposure, target engagement, unbound drug concentration, predictive biomarkers, and safety. Ion channels and transporters, including ANO1/TMEM16A, LRRC8/VRAC, KCa3.1, hERG, STIM-ORAI, TRP, and pH regulators, remain exploratory candidate targets. Available evidence for their role in acquired osimertinib resistance is largely indirect; expression or general tumor biology does not establish disease-specific dependency. A mechanism-matched development pathway using paired tissue and plasma sampling, relevant resistant models, causal perturbation, and pharmacodynamic validation is proposed. Clinical decisions should follow validated mechanisms rather than extrapolated biophysical hypotheses.