Lung carcinoma is the leading cause of cancer-related death in men and women in the United States. Despite advances in understanding the biology of lung cancer and introduction of several novel agents, 5 year survival remains at a dismal 15%. In order to enhance therapeutic strategies, we propose to target aberrant cell signaling in lung cancers with a primary focus on the mTOR pathway. Our program consists of 4 interconnected projects and 3 primary cores. The program projects include exploration of the mammalian target of rapamycin (mTOR) axis proteins and their importance in prognosis in lung cancer (primary aim - project 1), along with translating these biological findings into therapeutic advances in lung cancer patients alone and in combination with docetaxel. Project 2 targets LKB1, a tumor suppressor gene known to be inactivated or mutated in lung cancer, and its role as a key regulator of taxane-sensitivity and TOR pathway signaling. Project 3 examines the synergy between taxanes and farnesyl-transferase inhibitors and studies the mechanisms underlying synergy and resistance to this combination. Project 4 examines the 14-3-3 protein, key regulators of the mTOR axis (especially Akt), while testing a potential application of inhibiting the 14-3-3 function for enhancing lung cancer therapy. The projects are ably supported by an administrative core, a lung pathology and molecular analysis core, and biostatistics core. It contains 3 active clinical trials and assessment of biomarkers from the Neoadjuvant Trial of Chemotherapy Hope (NATCH) being conducted in Spain. The ultimate goal of this program project is three-fold: 1) to enhance efficacy of existing agents (taxanes); 2) to study novel signaling pathways that can be regulated by molecules in clinical trials (farnesyl-transferase inhibitors); 3) to develop completely novel approaches to lung cancer therapy through modulating LKB1 and 14-3-3 functions. Lung cancer is the leading cause of cancer-related death in men and women, both in the U.S. and worldwide. Only 15% of lung cancer patients are alive five years after diagnosis, even with new drugs. The proposed program consists of four interconnected projects, supported by three cores. We hope to improve lung cancer therapy by better understanding how lung cancer cells communicate, through the process called cell signaling. We will study these cell signaling pathways and how several drugs interfere with them, so that cancer cells cannot communicate and reproduce. We will also study tumor samples from a large international clinical trial and from our own clinical trials. We believe that this project can make important advances in determining which patients will do well with which therapies. We also hope to find new drugs that only target cancer cells and their altered signaling pathways, leaving healthy cells alone.