These mechanisms include aberrant EGFR activation, bypass signaling through the mesenchymal-epithelial transition receptor (MET) and SRC pathways, epithelial-mesenchymal transition (EMT), adaptive kinome remodeling, and exposure-associated inflammatory signaling, all of which may influence tumor evolution and therapeutic response.<h4>Conclusions</h4>This review introduces a novel exposome-driven conceptual framework integrating environmental exposures with signaling plasticity and resistance evolution in oncogene-driven NSCLC. The gene discussed is EGFR; the disease is neoplasm.