I?B Kinase ? Is Required for Development and Progression of KRAS-Mutant Lung Adenocarcinoma.

ABSTRACT: Although oncogenic activation of NF?B has been identified in various tumors, the NF?B-activating kinases (inhibitor of NF?B kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKK? and IKK? in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D Using NF?B reporter mice and conditional deletions of IKK? and IKK?, we identified two distinct early and late activation phases of NF?B during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, I?B?, and IKK? in tumor-initiated cells. IKK? was a cardinal tumor promoter in chemical and genetic KRAS-mutant lung adenocarcinoma, and respiratory epithelial IKK?-deficient mice were markedly protected from the disease. IKK? 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? 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? inhibitor. These results demonstrate an actionable requirement for IKK? in KRAS-mutant lung adenocarcinoma, marking the kinase as a therapeutic target against this disease.Significance: These findings report a novel requirement for IKK? in mutant KRAS lung tumor formation, with potential therapeutic applications. Cancer Res; 78(11); 2939-51. ©2018 AACR.

SUBMITTER: Vreka M 

PROVIDER: S-EPMC6485619 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature