Osimertinib Resistance in EGFR‐Mutated Non–Small Cell Lung Cancer: Mechanisms and Therapeutic Strategies

) mutations being one of the most common actionable genetic alterations. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), has significantly improved the prognosis of patients with EGFR-mutated NSCLC, but acquired resistance remains a major clinical obstacle limiting its long-term efficacy. This review summarizes key mechanisms of osimertinib resistance, including both EGFR-dependent and EGFR-independent resistance pathways. A major focus is placed on the chromatin remodeler Switch/Sucrose nonfermentable (SWI/SNF) related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), which mediates resistance through its interplay with EGFR signaling. Epigenetically, SMARCA4 loss modulates the tumor microenvironment and therapeutic response by triggering a stress-induced yet functionally impaired nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway and activating phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling. This cascade not only promotes tumor proliferation and survival but also directly confers resistance to osimertinib. Beyond SMARCA4, this review also discusses bypass pathway activation and further summarizes recent advances in novel targeted agents and combination therapies against osimertinib resistance. Overall, it provides an integrated overview of resistance mechanisms and supports the development of improved precision therapies for EGFR-mutant NSCLC.