Based on evidence that the Wnt–β-catenin and Notch3 pathways play a part in tumorigenesis and that there is an interaction between FOXO3a and β-catenin, we speculate that Notch3 controls the expression of FOXO3a through non-classical dependence on β-catenin in lung cancer cell resistance, thereby regulating EGFR signal. This evidence concerns the gene NOTCH3 and lung cancer.