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

Suicide gene vectors are being developed in many laboratories as an attractive approach to cancer therapy. However, the development of these therapies is hampered by safety concerns and limitations of efficacy. The use of tumor-specific promoters, such as survivin promoter, can provide much needed specificity to target tumor cells. However, the expression levels from these promoters is often suboptimal and hence it is imperative to enhance the activity of the cytotoxic gene of interest. We tested apoptotic activity of several mutants of proapoptotic gene bax that constitutively translocate to the mitochondria and induce apoptosis. One of these mutants with deletion of serine at position S184 (S184del) was found to be most active and showed significant antitumor activity when expressed by the survivin promoter. In vitro testing shows that this vector (Sur-BaxS184del) induces cell killing in a variety of tumor cell lines of different origin with significantly higher efficacy than wild-type bax (SurBaxWT). The increase in cytotoxicity was a result of enhanced induction of apoptosis in tumor cells. In contrast to cytomegalovirus (CMV) promoter-driven bax (CMV-Bax), Sur-BaxS184del caused minimum toxicity in normal human dermal fibroblasts validating its specificity and safety. In a mouse tumor model (DA-3, murine breast cancer cells), we show that intratumoral injection of SurBaxS184del resulted in tumor growth retardation to the same level as CMV-Bax. This study highlights the effectiveness of using bax mutants in combination with survivin promoter for tumor-targeted suicide gene therapy in a nonviral vector.