IL-22 Confers Resistance To Gefitinib In Non-small Cell Lung Cancer Bearing EGFR Gene Mutation And Amplification

Objective: The effect of epidermal growth factor receptor(EGFR)-targeted strategy is hindered by drug resistance.IL-22 can promote tumor growth and induce resistance to chemotherapy in human lung cancer cells.The aim of our study was to investigate the mechanism of IL-22-induced resistance to EGFR-TKIs in the non-small cell lung cancer(NSCLC).Materials and methods: The tissues and plasma of patients taking EGFR-TKIs were used to examine the correlation between the drug's efficacy and IL-22 level.We identified IL-22-induced EGFR-TKIs resistance and the effect of IL-22 on EGFR and PI3K/AKT and MEK/ERK1/2 signaling pathways in NSCLC PC-9 and HCC827 cells by CCK-8 assay,flow cytometric analysis,and western blot.Then,we established the PC-9 xenograft model with IL-22 alone,gefitninb alone,IL-22 in combination with Gefitinib.the tunlor growth,weight of mice,EGFR signal pathway related protein expression were observed.Results: IL-22 expression was correlated with acquired resistance to EGFR-TKIs in human lung cancer tissues and plasma(P<0.05).IC50 values of IL-22 in gefitinib group was lower than that of IL-22 combined with gefitinib group(PC-9 :0.065±0.016?m vs.0.26±0.021?m,P = 0.002;HCC827 : 0.02±0.0029?m vs.1.11±0.12?m,P=0.001).The cell apoptosis rate of gefitinib group was higher than that of IL-22 combined with gefitinib group(PC-9:36.47% vs.20.41%,P=0.009;HCC827:34.86% vs.21.16%,P=0.003).Gefitinib inhibited the expression of p-EGFR,p-AKT and p-ERK,and the aforementioned effects of gefitinib were suppressed by IL-22.The above results were verified in PC-9 nude mice xenograft model.The tumor volume and weight of gefitinib combined with IL-22 group was higher than those of gefitinib group(P(volume)=0.011;P(weight)=0.008).Conclusions: These results suggest that IL-22 contributes to tumor progression and EGFR-TKIs resistance in NSCLC.Therefore,IL-22 is a potential therapeutic target for EGFR-TKIs resistance.