Although oncogenic activation of NFkappaB has been identified in various tumors, the NFkappaB-activating kinases (inhibitor of NFkappaB kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKalpha and IKKbeta in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRAS(G12D) Using NFkappaB reporter mice and conditional deletions of IKKalpha and IKKbeta, we identified two distinct early and late activation phases of NFkappaB during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, IkappaBbeta, and IKKalpha in tumor-initiated cells. IKKalpha was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKKalpha-deficient mice were markedly protected from the disease. IKKalpha 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 IKKalpha 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 IKKbeta inhibitor. These results demonstrate an actionable requirement for IKKalpha in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease.Significance: These findings report a novel requirement for IKKalpha in mutant KRAS lung tumor formation, with potential therapeutic applications. Cancer Res; 78(11); 2939-51. (c)2018 AACR.
- Vreka, M.
- Lilis, I.
- Papageorgopoulou, M.
- Giotopoulou, G. A.
- Lianou, M.
- Giopanou, I.
- Kanellakis, N. I.
- Spella, M.
- Agalioti, T.
- Armenis, V.
- Goldmann, T.
- Marwitz, S.
- Yull, F. E.
- Blackwell, T. S.
- Pasparakis, M.
- Marazioti, A.
- Stathopoulos, G. T.
