Herein, we show that IKKα expressed in lung epithelial cells functions as a major tumor suppressor of NSCLC development and progression in two independent in vivo models: (1) lung adenomas induced by urethane carcinogen in mice with an inducible IKKα deletion targeted solely in AT-II (alveolar type II) lung epithelial cells and (2) a panel of IKKα knockdown human NSCLC lines (harboring either wild-type or mutant K-Ras and p53 genes) grown as tumor xenografts in immune-compromised NSG mice. This evidence concerns the gene TP53 and neoplasm.