This study demonstrated for the first time that the ARL4C/JAK2/STAT5/β-catenin axis and their downstream molecules Axin2, CD44, Ccnd1, Lgr-5, and MMP7 could help to bypass EGFR oncogenic path and serve as an alternative new signal/function path to maintain the survival and malignant behaviors for HCC827 and PC9 NSCLC cells under the stress of Erlotinib. This evidence concerns the gene JAK2 and non-small cell lung carcinoma.