Lung cancer is the leading cause of cancer death in the U.S. and the world with approximately 90% of lung cancer patients expected to die of the disease. The majority (80%) of these tumors are non-small cell lung cancer (NSCLC). This indicates that new and highly relevant genetic targets are needed for improvements in diagnosis and treatment of these tumors. We have identified the FOXO3a gene as a candidate tumor suppressor gene based on its frequent deletion in lung adenocarcinomas. FOXO3a is a stress responsive transcription factor whose cellular role depends on its ability to either activate or repress a large body of genes. Our results show that its role in lung tumor suppression involves the protection of lung epithelia from carcinogen-induced DNA damage. It protects against this major cause of lung cancer by activating stress-induced apoptosis. Many of the drugs currently used to treat adenocarcinomas are likely to engage FOXO3a-induced apoptosis as well, including direct (platinum-based) and indirect (topoisomerase inhibitors) DNA damaging agents, and antimitotics (taxanes and vinca alkaloids). FOXO3a also functions as an antagonist of the EGFR/P13K/Akt pathway, which is of high relevance in lung tumorigenesis and lung cancer treatment. Therefore, FOXO3a status is expected to influence the efficacy of new therapeutics that target EGFR and PI3K in lung adenocarcinomas as well. Hence, the functions of FOXO3a, and the genes it regulates, in tumor suppression are very likely to significantly affect treatment response, and may predict treatment outcome. We hypothesize that FOXO3a gene status in lung adenocarcinomas predicts the treatment outcome of several drugs currently used to treat these tumors. Also, critical effectors of FOXO3a that are involved in drug-induced tumor cell killing are potential targets in the treatment of these tumors, particularly in cases where FOXO3a function is reduced or lost (~50% of tumors). This hypothesis will be tested through the following Specific Aims: (1) Determine whether FOXO3a predicts sensitivity to therapeutic agents used to treat human lung adenocarcinomas. (2) Identify novel transcriptional targets of FOXO3a that control the anti-tumor response to lung cancer therapeutic agents. Advances in lung cancer treatment are greatly needed to reduce its 90% mortality rate. We anticipate that the outcome of this study will contribute to this progress.