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.
Item Type: | Journal article |
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Faculties: | Medicine |
Subjects: | 600 Technology > 610 Medicine and health |
ISSN: | 0008-5472 |
Language: | English |
Item ID: | 65177 |
Date Deposited: | 19. Jul 2019, 12:17 |
Last Modified: | 04. Nov 2020, 13:45 |