I{kappa}B kinase {alpha} is required for development and progression of KRAS-mutant lung adenocarcinoma.

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

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader https://ift.tt/2DYQBRt