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IL-22 Confers EGFR-TKI Resistance in NSCLC via the AKT and ERK Signaling Pathways.

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.

SUBMITTER: Wang X

PROVIDER: S-EPMC6848259 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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IL-22 Confers EGFR-TKI Resistance in NSCLC via the AKT and ERK Signaling Pathways.

Wang Xiaomeng X Xu Jiali J Chen Jin J Jin Shidai S Yao Jiaqi J Yu Tongfu T Wang Wei W Guo Renhua R

Frontiers in oncology 20191105

<b>Background:</b> 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. <b>Methods:</b> The plasma and tissues of patients who received EGFR-TKIs were utilized to determine the association between IL-22 expression ...[more]

PMID: 31750252

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Project description:PurposeWe aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations.Materials and methodsThis multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint.ResultsThe overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment.ConclusionEGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Dataset Information

IL-22 Confers EGFR-TKI Resistance in NSCLC via the AKT and ERK Signaling Pathways.

Publications

IL-22 Confers EGFR-TKI Resistance in NSCLC via the AKT and ERK Signaling Pathways.

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