In the meantime, these data establish new insights into the functional interaction among EGFR, Notch3, β-catenin, and FOXO3a: Notch3 is activated when EGFR-TIK inhibits EGFR and then stimulates β-catenin in a non-classical way, and β-catenin acts on EGFR in combination with FOXO3a; therefore, inhibition of Notch3 provides a potential combined treatment strategy for EGFR-TIK-resistant lung cancer. Here, EGFR is linked to lung cancer.