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Cancer patients who initially benefit from Erlotinib, a drug targeting  EGFR  path, eventually develop resistance to the drug. The underlying mechanism is largely unknown. This study investigated the role of  ARL4C  in Erlotinib resistance development of NSCLC. qRT-PCR and Western blotting were performed to analyze the expression of mRNA and protein of  ARL4C  in two NSCLC cell lines (HCC827 and PC-9). Several assays (MTS, colony formation, transwell migration, luciferase reporter, and chromatin-immunoprecipitation) were used to explore the role of  ARL4C  in biofunctional changes of Erlotinib-resistant cells and their associations with  Jak2/Stat 5/ β -catenin  signaling. Results demonstrated that (1) long-term use of Erlotinib resulted in downregulation of  ARL4C ; (2) overexpression of ARL4C could regain the sensitivity to Erlotinib in the drug-resistant HCC827/ER cells, while downregulation of  ARL4C  increased HCC827, and PC-9 cells' resistance to the drug; (3) Erlotinib-induced downregulation of  ARL4C  resulted in phosphorylation of  Jak2/Stat5  and upregulation of β -catenin  and their related molecules  Axin2, CD44, Ccnd1, Lgr-5 , and  MMP7 , which promoted the malignant behaviors of Erlotinib-resistant cells; (4) chromatin immunoprecipitation and luciferase reporter assay revealed that Stat5 could bind to β -catenin  promoter to upregulate molecules to maintain the malignant behaviors, which might count for how Erlotinib-resistant cell survived while  EGFR  path was blocked; (5) the expression of  ARL4C  was not associated with known EGFR gene mutations in both Erlotinib-resistant cells and NSCLC tissues. Our data suggest that Erlotinib resistance of NSCLCs is associated with downregulation of  ARL4C  via affecting  Jak/Stat/ β -catenin  signaling.  ARL4C  could serve as a biomarker to predict the effectiveness of TKI targeting therapy and a potential therapeutic target for overcoming Erlotinib resistance in NSCLC.

The Role of ARL4C in Erlotinib Resistance: Activation of the Jak2/Stat 5/β-Catenin Signaling Pathway