Strategies of overcoming osimertinib resistance in EGFR-mutated non-small cell lung cancer

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has significantly advanced the treatment of non-small cell lung cancer (NSCLC), particularly in patients who develop resistance to first- and second-generation EGFR-TKIs. However, most patients inevitably develop resistance to the treatment, which presents a major challenge for long-term disease control. The molecular mechanisms underlying osimertinib resistance are complex and are generally categorised into EGFR-dependent and EGFR-independent pathways. To address this issue, various therapeutic strategies have been explored. These include the development of fourth-generation EGFR-TKIs, novel targeted agents and combination therapies involving molecular inhibitors, chemotherapeutic drugs, immunotherapeutic agents and gene inhibitors. In addition, nanomaterials, particularly selenium nanoparticles (SeNPs), have emerged as promising tools to overcome drug resistance. These nanomaterials can be used to enhance osimertinib delivery, improve its bioavailability, and modulate key resistance pathways at the cellular and molecular levels. This review comprehensively summarises the current understanding of resistance mechanisms to osimertinib and highlights cutting-edge therapeutic approaches. Special attention is given to nanotechnology-based strategies, which offer new possibilities for personalised and precise treatment of NSCLC. A deeper insight into these molecular mechanisms is essential for improving the clinical efficacy of osimertinib and prolonging the survival of patients with EGFR-mutant NSCLC.