ArticleArchives of pharmacal research2023
Selumetinib overcomes gefitinib primary and acquired resistance by regulating MIG6/STAT3 in NSCLC.
Article in Archives of pharmacal research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 7 citations in OpenAlex.
- A pH-responsive silver nanoparticle platform overcomes MEK inhibitor resistance in neurofibroma via triacsin C-mediated lipid metabolic reprogramming.Apoptosis : an international journal on programmed cell death · 2026Article
- Pathomic model to predict the expression of UQCRH and overall survival of lung adenocarcinoma patients.Diagnostic pathology · 2026Article
- Adaptive Proteomic Changes in Protein Metabolism and Mitochondrial Alterations Associated with Resistance to Trastuzumab and Pertuzumab Therapy in HER2-Positive Breast Cancer.International journal of molecular sciences · 2025Article
- Itraconazole Reversing Acquired Resistance to Osimertinib in NSCLC by Inhibiting the SHH/DUSP13B/p-STAT3 Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Tanreqing injection inhibits stemness and enhances sensitivity of non-small cell lung cancer models to gefitinib through ROS/STAT3 signaling pathway.Journal of Cancer · 2024Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Gefitinib, as the first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore, exploring the resistance mechanism of gefitinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC with gefitinib. Selumetinib also enhanced gefitinib-induced apoptosis and migration inhibition ability in gefitinib-resistant lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verified through the STRING database and western blotting assays. Sustained activation of STAT3 was significantly downregulated when co-treatment with selumetinib in gefitinib-resistant cells. However, the downregulation of p-STAT3, resulting from the combination of selumetinib and gefitinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced gefitinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with gefitinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and gefitinib effectively promoted the sensitivity of lung cancer xenografts to gefitinib in vivo, and the tumor inhibition rate reached 81.49%, while the tumor inhibition rate of the gefitinib monotherapy group was only 31.95%. Overall, MIG6/STAT3 negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be beneficial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.
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