Abstract
Background: The efficacy of an EGFR-targeted treatment strategy for non-small cell lung cancer (NSCLC) is reduced by drug resistance. IL-22 enhances tumor growth and induces chemotherapy resistance in human lung cancer cells. The present study elucidated the IL-22-induced mechanism underlying EGFR-tyrosine kinase inhibitor (TKI) resistance in NSCLC.Methods: The plasma and tissues of patients who received EGFR-TKIs were utilized to determine the association between IL-22 expression and gefitinib efficacy. The IL-22 effect on the EGFR/ERK/AKT pathways in NSCLC HCC827 and PC-9 cells was determined using the CCK-8 assay, western blot, and flow cytometric analysis. A PC-9 xenograft model of IL-22 exposure was established. Gefitinib was administered to mice in combination with IL-22 or vehicle.Results: We showed that IL-22 expression was higher in the EGFR-TKI-resistant group compared to EGFR-TKI-sensitive group. IL-22 expression was associated with EGFR-TKI efficacy in plasma. Additional treatment of IL-22 induced gefitinib resistance and reduced apoptosis in PC-9 and HCC827 cell lines. Furthermore, we showed that the effects of IL-22 attributed to p-ERK, p-EGFR, and p-AKT up-regulation. IL-22 neutralizing antibody completely abrogated the effects of IL-22 on apoptosis and AKT/EGFR/ERK signaling. Finally, we showed that IL-22 enhanced tumor growth and induced gefitinib resistance in the PC-9 xenograft model. Moreover, compared with gefitinib alone, the combination of IL-22 and gefitinib led to an increase in Ki67-positive staining and a reduction in TUNEL staining.Conclusions: Our findings indicate that IL-22 plays a role in tumor progression and EGFR-TKI resistance in NSCLC. Thus, IL-22 might serve as a novel biomarker to overcome resistance of EGFR-TKI.
Highlights
Lung cancer is a main cause of cancer mortality globally, and is responsible for 1.6 million deaths every year [1]
All of the samples had EGFR mutations involving an exon 19 deletion (19DEL) or exon 21 mutation (L858R) among patients who were treated with an EGFR-tyrosine kinase inhibitor (TKI) from March 2015 to August 2017
The IL-22 mRNA level was lower in the EGFR-TKIsensitive group than the acquired resistance group (P < 0.01; Figure 1A)
Summary
Lung cancer is a main cause of cancer mortality globally, and is responsible for 1.6 million deaths every year [1]. Secondary-site EGFR mutations, most of which are T790M, are the major cause of acquired resistance (∼60%). Immune checkpoint (programmed death 1 [PD1] and programmed death-ligand 1 [PD-L1]) inhibitors have been tried for these patients, no satisfactory efficacy was achieved so far. Despite these efforts, the mechanisms of EGFRTKI resistance are not fully understood. There is enormous need to develop innovative treatment strategies based on the mechanism underlying EGFR-TKI resistance. The efficacy of an EGFR-targeted treatment strategy for non-small cell lung cancer (NSCLC) is reduced by drug resistance. The present study elucidated the IL-22-induced mechanism underlying EGFR-tyrosine kinase inhibitor (TKI) resistance in NSCLC
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