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Vreka, Malamati; Lilis, Ioannis; Papageorgopoulou, Maria; Giotopoulou, Georgia A.; Lianou, Marina; Giopanou, Ioanna; Kanellakis, Nikolaos I.; Spella, Magda; Agalioti, Theodora; Armenis, Vasileios; Goldmann, Torsten; Marwitz, Sebastian; Yull, Fiona E.; Blackwell, Timothy S.; Pasparakis, Manolis; Marazioti, Antonia; Stathopoulos, Georgios T. (2018): I kappa B Kinase alpha Is Required for Development and Progression of KRAS-Mutant Lung Adenocarcinoma. In: Cancer Research, Vol. 78, No. 11: pp. 2939-2951
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Abstract

Although oncogenic activation of NF kappa B has been identified in various tumors, the NF kappa B-activating kinases (inhibitor of NF kappa B kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKK alpha and IKK beta in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D. Using NF kappa B reporter mice and conditional deletions of IKK alpha and IKK beta, we identified two distinct early and late activation phases of NF kappa B during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, I kappa B beta, and IKK alpha in tumor-initiated cells. IKK alpha was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKK alpha-deficient mice were markedly protected from the disease. IKK alpha 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. IKK alpha 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 IKK beta inhibitor. These results demonstrate an actionable requirement for IKK alpha in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease. Significance: These findings report a novel requirement for IKK alpha in mutant KRAS lung tumor formation, with potential therapeutic applications.