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  • Title: Cyclosporine A sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of STAT3.
    Author: Shou J, You L, Yao J, Xie J, Jing J, Jing Z, Jiang L, Sui X, Pan H, Han W.
    Journal: Cancer Lett; 2016 Aug 28; 379(1):124-33. PubMed ID: 27264264.
    Abstract:
    The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have dramatically prolonged the overall survival of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutation, but the presence of primary or acquired resistance eventually leads to therapeutic failure. Thus, how to improve the efficacy and reverse the resistance to EGFR-TKIs remains a significant challenge. In this study, we found that CsA significantly augmented the anti-cancer effect of gefitinib in EGFR-TKI-sensitive and -resistant NSCLC cells. Mechanistically, CsA promoted gefitinib-induced apoptosis through inhibition of the STAT3 pathway. Similar with the function of CsA, siRNAs against STAT3 also enhanced gefitinib-induced apoptosis in multiple lung cancer cells. Xenograft studies further demonstrated that CsA promoted the anti-cancer activity of gefitinib on lung cancer cells through inhibition of STAT3. Moreover, NSCLC patients with high levels of phosphorylated STAT3 (Y705) showed a significantly poorer therapeutic response to EGFR-TKIs. This study provides preclinical evidence that the combination of CsA or a STAT3 inhibitor with EGFR-TKIs is a promising approach to improve the efficacy of EGFR-TKIs for the treatment of patients with advanced NSCLC.
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