Lung cancer is the leading cause of cancer-related death in the United States. The most common subtype is non-small cell lung cancer (NSCLC), making up ~85% of cases. Multiple subtypes of NSCLC have been identified, and while they have been treated historically as the same disease, it is now recognized that these subtypes have distinct responses to therapy. In particular, the squamous cell carcinoma (SCC) subtype is refractory to current therapies and is responsible for the death of ~40,000 people each year in the United States. Effective targeted therapies for SCC are currently lacking.

Creation of a mouse model of SCC is essential for (1) identifying genes and pathways that cause SCC, (2) testing new therapeutic strategies for SCC, and (3) elucidating mechanisms of drug resistance.

Recent efforts in large-scale genomic sequencing of human SCC have identified recurrent mutations and genomic alterations that are likely responsible for promoting SCC. We will create a mouse model of SCC by introducing common SCC mutations and gene alterations into the mouse lung using sophisticated viral delivery systems. We will also promote tumors in different lung cell types to determine how the cell of origin ultimately influences tumor characteristics. State-of-the-art imaging technologies will be used to identify lung tumors in living animals. We predict that these genes will promote SCC lung tumors and will establish a model in which to test new therapeutic targets and drug resistance mechanisms for this intractable subtype of human lung cancer.