Osimertinib acquired resistance among patients with EGFR-mutated NSCLC: from molecular mechanisms to clinical therapeutic strategies.

Non-small-cell lung cancer (NSCLC) remains the leading cause of global cancer-related mortality. NSCLC patients with epidermal growth factor receptor (EGFR) mutations benefit substantially from treatment with EGFR tyrosine kinase inhibitors, particularly osimertinib. Although recent clinical trials have established osimertinib as effective treatment across many stages of EGFR-mutant NSCLC, the inevitable emergence of acquired resistance poses a major therapeutic challenge despite the substantial clinical benefit. Understanding the mechanisms of osimertinib acquired resistance is urgently needed to identify effective strategies to overcome it. Resistance to osimertinib including on-target mechanisms such as novel EGFR secondary mutation, off-target mechanisms such as mesenchymal-epithelial transition or human EGFR 2 amplification, mutations in downstream signaling molecules, and oncogenic fusions, and the Histological transformations (such as epithelial-mesenchymal transition, squamous cell carcinoma, or small cell lung cancer) have been well described. This review summarizes the mechanisms and clinical significance of osimertinib-acquired resistance in recent years, as well as new clinical treatments. It is expected to provide valuable insights and potential new strategies for the clinical treatment of EGFR-mutated NSCLC patients with osimertinib resistance.