Abstract 2873: Epithelial NF-κB signaling is required for different functions in Kras- and EGFR-mediated lung tumorigenesis

The transcription factor nuclear factor-κB (NF-κB) is a key mediator of the inflammatory response, and its activation correlates with poor prognosis in non-small cell lung cancer patients. Oncogenic KRAS and epidermal growth factor receptor (EGFR) mutations occur frequently in lung adenocarcinoma and are associated with increased NF-κB activation in lung tumors. Recent papers have shown that inhibition of epithelial NF-κB signaling in a mouse model of Kras-mediated lung tumorigenesis decreases tumor formation. However, the mechanisms linking NF-κB signaling to tumor formation remain unclear. We hypothesize that epithelial NF-κB signaling is a common requirement for lung tumorigenesis. For our studies, we used mice that inducibly express oncogenic KrasG12D or EGFRL858R+T790M as well as a dominant negative inhibitor of κB signaling (DN-IκB) in Clara Cell Specific Protein (CCSP)-expressing lung epithelium (designated KrasDN or EGFRDN mice). EGFRDN mice developed smaller and fewer tumors after two months of doxycycline administration compared to mice expressing EGFRL858R+T790M alone, while KrasDN mice did not develop any tumors. In KrasDN mice, loss of Kras transgene expression and increased cell death were observed after one week of doxycycline, suggesting that NF-κB signaling may be required for survival of Kras mutant cells in vivo. In EGFRDN mice, NF-κB inhibition led to a significant reduction in the percentage of BAL neutrophils when compared to mice expressing EGFRL858R+T790M alone. In addition, NF-κB inhibition led to reduced expression of CXCR2 ligands CXCL1 and CXCL2, which are known NF-κB-regulated neutrophil chemoattractants. In vitro inhibition of CXCR2 did not affect proliferation of EGFR-mutant cells, suggesting that the critical function of CXCL1 and CXCL2 may be inflammatory cell recruitment/activation. Future studies will investigate the effects of CXCR2 inhibition and neutrophil depletion on EGFR-mediated tumor formation in vivo. Together, these results suggest that NF-κB signaling is required for both Kras- and EGFR-mediated lung tumorigenesis, but NF-κB's function in a tumor may depend on the driver mutation. From these studies, we hope to identify NF-κB-regulated genes critical for tumor formation as potential targets for the development of better therapeutic strategies for lung cancer patients. Citation Format: Jamie A. Ausborn, Taylor Sherrill, Rinat Zaynagetdinov, Vasiliy Polosukhin, Frank McMahon, Fiona Yull, Timothy Blackwell. Epithelial NF-κB signaling is required for different functions in Kras- and EGFR-mediated lung tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2873. doi:10.1158/1538-7445.AM2013-2873