Finally, our results proved that stemness (KLF4 and FGFR2) and epithelial–mesenchymal transition (ZEB2, TWIST2, SNAI2, CDH2, and VIM) factors, which are highly expressed in PC9GR cells compared to gefitinib-sensitive PC9 cells, could be abrogated with the neddylation inhibitor MLN4924 mainly through activation of epithelial differentiation pathways, thus exerting a protective role in lung cancer cells and chemosensitivity against lung tumorigenic transformation. Here, KLF4 is linked to lung cancer.