Lung cancer is the leading cause of cancer-related death in the US and worldwide.  For patients with metastatic non-small cell lung cancer (NSCLC), median survival is 10-12 months with chemotherapy.  However, in a subset of NSCLC patients – those whose tumors harbor mutations in the gene encoding the epidermal growth factor receptor (EGFR) – patients can live much longer with fewer side-effects by treatment with selective EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) and Tarceva (erlotinib).  Unfortunately, though, despite killing tumor cells, Iressa and Tarceva do not cure patients in the metastatic setting.  The overall goal of this proposal is to identify ways to improve even further the outcome of these patients.  We believe a better understanding of how mutant EGFR-dependent cells actually “die” when treated with TKIs will help us develop new strategies to enhance drug-induced tumor cell killing.  In our preliminary studies, we have identified a molecule whose activation is necessary for Tarceva to induce cell death.  Thus, using human lung cancer cell lines, mouse model systems, and a variety of cellular, biochemical, and molecular techniques, the overall aims of this project are to enhance further our understanding of mechanisms that control TKI-induced cell death and to establish whether drugs that “sensitize” killing by affecting a specific cell death pathway can potentiate TKI-induced killing.  Since this new class of drugs is now being tested in early phase clinical trials, our studies could have direct and immediate translational impact.