Core Viewpoint - Drug resistance remains the most severe challenge in targeted therapy for lung cancer, with cuproptosis showing promise in overcoming this resistance, although its potential in targeted treatment has yet to be fully explored [1]. Group 1: Research Findings - A study published by researchers from the Chinese Academy of Medical Sciences indicates that inducing cuproptosis enhances the sensitivity of lung cancer to the targeted drug osimertinib and overcomes drug resistance [2][3]. - The research team observed a high degree of synergistic effect between CuET (copper death induction) and osimertinib, indicating that cuproptosis induction increases the anticancer efficacy of osimertinib [5]. - In a secondary screening, cuproptosis was identified as a major vulnerability in osimertinib-resistant cell lines, with the key driver factor FDX1 significantly upregulated in these resistant cells [6]. Group 2: Mechanism of Action - The study highlights that the activation of bypass pathways, particularly involving AKT phosphorylation, is the most common mechanism of drug resistance, accounting for approximately 46% of cases [7]. - Induction of cuproptosis in combination with osimertinib significantly reduced p-AKT levels while increasing the expression of cuproptosis markers and apoptosis markers, suggesting a mechanism for overcoming drug resistance [7]. - In patient-derived organoid models, the combination of CuET and osimertinib outperformed single-agent treatments, demonstrating the potential for enhanced therapeutic efficacy [8]. Group 3: Clinical Implications - The findings suggest that targeting cuproptosis could be a promising strategy to overcome osimertinib resistance, linking it to the commonly overlooked AKT activation mechanism [10]. - With the development of copper ion carriers and nanoparticle delivery systems being actively pursued, these discoveries provide a pathway for clinical translation, necessitating prospective trials to evaluate safety and efficacy [10].