IκB Kinase α is required for development and progression of KRAS-mutant lung adenocarcinoma

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

Fine-tuning lung cancer nanotherapy using closed cardiopulmonary circulation.

Statement of Purpose: Lung cancer is the leading cause of cancer-related deaths and efficient therapies remain elusive. One emerging approach is to use nanoparticles (NPs) that are designed to specifically target malignant cells (1). Such targeting increases on-site drug doses and reduces systemic side effects. A common target in lung tumors is epidermal growth factor receptor (EGFR). Here, we explored the targeting efficacy of EGFR-targeted mesoporous silica nanoparticles (MSN GE11 ) for lung cancer treatment. Though specifically taken up by cancer cells in vitro, when administered intravenously or intratracheally in lung cancer mouse models, the NPs could not reach the depths of solid tumors and often strayed away from their target. This raises concerns whether NPs are suitable for therapeutically targeting lung tumors and challenges translational value of current approaches. To circumvent physiological barriers of solid lung tumors and consequent systemic clearance of NPs, we extended our analysis to a treatment strategy where the NPs are administered intravenously in a closed cardiopulmonary (CP) circulation loop. This approach not only makes the therapy more local, but also eliminates confounding factors for NP delivery such as liver/spleen deposition of NPs in vivo