Simple SummaryNon-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer and epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of NSCLC. The aim of our study was to evaluate the impacts of the proinflammatory cytokine, interleukin (IL)-17A, on EGFR-mediated progression of NSCLC. In NSCLC cells with mutant EGFR, we found that the IL-17A/IL-17 receptor C (IL-17RC) axis enhanced phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-tyrosine kinase inhibitors (TKIs). In NSCLC cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing an impairment of EGF-induced EGFR lysosomal degradation. Our results indicated that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for NSCLC treatment.AbstractNon-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common pathological subtype. Epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR-tyrosine kinase inhibitors (TKIs). The proinflammatory cytokine, interleukin (IL)-17A, and IL-17A-producing cells were reported to be elevated in the tumor microenvironment and peripheral blood of NSCLC patients and to be correlated with tumor progression and poor prognoses. However, the pathophysiological role of IL-17A in NSCLC remains unclear, although some studies suggested its involvement in cancer cell invasion and metastasis. Herein, we observed that expressions of IL-17A and its receptor, IL-17 receptor C (IL-17RC), were elevated in LUAD tissues and were correlated with poor survival in different lung cancer cohorts. In LUAD cells with mutant EGFR, the IL-17A/IL-17RC axis was shown to enhance phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-TKIs such as afatinib. In LUAD cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing impairment of EGF-induced EGFR lysosomal degradation. Collectively, our results indicated diverse impacts of the IL-17A/IL-17RC axis on EGFR activation in LUAD cells with WT and mutant EGFR and suggested that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for LUAD treatment.