IkB kinase a Is required for development and progression of KRAS-mutant lung adenocarcinoma

© 2018 American Association for Cancer Research. Although oncogenic activation of NFkB has been identified in various tumors, the NFkB–activating kinases (inhibitor of NFkB kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKa and IKKb in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D. Using NFkB reporter mice and conditional deletions of IKKa and IKKb, we identified two distinct early and late activation phases of NFkB during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, IkBb, and IKKa in tumor-initiated cells. IKKa was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKKa-deficient mice were markedly protected from the disease. IKKa specifically cooperated with mutant KRAS for tumor induction in a cell-autonomous fashion, providing mutant cells with a survival advantage in vitro and in vivo. IKKa was highly expressed in human lung adenocarcinoma, and a heat shock protein 90 inhibitor that blocks IKK function delivered superior effects against KRAS-mutant lung adenocarcinoma compared with a specific IKKb inhibitor. These results demonstrate an actionable requirement for IKKa in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease. Significance: These findings report a novel requirement for IKKa in mutant KRAS lung tumor formation, with potential therapeutic applications.