Abstract 1083: The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas.

During the last decades lung cancer has become the leading cause of cancer deaths in the world, and the need to develop better diagnostic techniques and therapies is urgent. To advance the understanding of this disease, various genetically engineered and chemical induced mouse models have been established. However, there are no robust animal models of lung squamous cell carcinomas (SCCs), one of the major types of lung cancer. Here, we generated Ikkα-KA/KA knock-in mice (KA/KA) in which an ATP binding site of IKKα, Lys 44 was replaced by alanine. All the knock-in mice at 4 to 6 months of age developed spontaneous lethal lung SCCs associated with markedly increased leukocyte infiltration and expression of cytokines, and chemokines in the lungs. Furthermore, we identified deregulated c-myc, Nanog, Oct3/4, p53, Rb, EGFR, MAPK, Jun-B, p63, Trim29, Rhov, CDK1, and IGF1 in mouse lung SCCs, and identified reduced IKKα and IκBα and increased ROS1 in mutant lungs and SCCs, some of which were found in human lung SCCs. Lung cancers were prevented by reintroducing epithelial-cell IKKα, depleting macrophages or depleting lymphocytes. This study not only provides a novel model for studying the pathogenesis, treatment, early detection, and prevention of human lung SCCs, but also demonstrates how a single mutation in IKKα elicits malignancy through the combined epithelial-cell-autonomous and immune mechanisms. Citation Format: Zuoxiang Xiao, Qun Jiang, Jami Willette-Brown, Feng Zhu, Sichuan Xi, Sandra Burkett, Fanching Lin, Timothy Back, Mahesh Datla, Zhonghe Sun, Romina Goldszmid, Xiaolin Wu, David Schrump, Howard Young, Georgio Trinchieri, Robert Wiltrout, Yinling Hu. The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas. [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 1083. doi:10.1158/1538-7445.AM2013-1083