The translational research on patients with adenocarcinoma of the lung here at the Dana- Farber/Harvard Cancer Center has helped identify patient subsets that respond differently to targeted agents. Women, patients with adenocarcinoma, and those who do not smoke cigarettes are more likely to have a favorable response to gefitinib and erlotinib therapy (Iressa and Tarceva) than patients with other types of lung cancer and men respectively. This prompted my laboratory to assemble tumor cell lines from women with adenocarcinoma who either did or did not smoke cigarettes to characterize their response to gefitinib. A team composed of our laboratory and the laboratory led by Dr. Sellers and Meyerson at the Dana-Farber Cancer Institute discovered that most patients who have a clinical response to gefitinib treatment have either point mutations or deletion of amino acids from the tyrosine kinase domain of the epidermal growth factor receptor. Our laboratory showed lung cancer cell lines with epidermal growth factor cell lines with these point mutations or deletions are 100 fold more sensitive to treatment gefitinib than cell lines with wild type sequence of the epidermal growth factor receptor. The lung cancer cell lines with mutations in the epidermal growth factor receptor treated with 100 nM of gefitinib have downregulation of phosphorylated epidermal growth factor receptor. This also leads to downregulation of the downstream targets including phospho-Akt and phospho-Erk1/2 kinase. Treatment of lung cancer cells with mutated epidermal growth factor receptor with 1 micromolar gefitinib leads to apoptosis while the cells with wild type epidermal growth factor receptor undergo a G1/S arrest. Future studies will study the relationship between different mutations in the epidermal growth factor receptor, their susceptibility to different epidermal growth factor receptor inhibitors, and the signaling pathways. Prospective trials will test the impact of these epidermal growth factor receptor mutations on the treatment of patients with non-small cell lung cancer. The studies will include erlotinib treatment in previously untreated elderly patients with advanced non-small cell lung cancer (older than 70) and women with adenocarcinoma who are either never smokers or former smokers. These patients will have their tumor DNA studied for the epidermal growth factor receptor sequence, and their response, response duration, subsequent response to other chemotherapy, and survival will be recorded. This will be done to determine if there is a relationship between the epidermal growth factor receptor sequence and the outcome of patients with non-small cell lung cancer after treatment with erlotinib.