Lung Cancer Program Project Summary / Abstract The Lung Cancer Program conducts innovative research on lung cancer causes and pathogenesis, focusing on discoveries that improve prevention, diagnosis, and therapy. The Program leverages expertise across all DF/HCC institutions in smoking cessation, lung cancer screening, genetic susceptibility, genomic changes in lung cancer, preclinical and clinical studies of novel therapies, and molecular analysis of tumors before and after targeted and immunotherapeutic agents. A core strength of the Program is an integral bidirectional link between the laboratory and clinic, which has enabled insights into drug resistance and accelerated clinical development of agents to overcome newly identified vulnerabilities. Community engagement is embedded in the Program’s laboratory, preventive, cancer screening, and clinical efforts. The Program’s 69 members (51 primary and 18 secondary) represent six DF/HCC institutions and 11 academic departments. In 2019, peer-reviewed grant funding attributed to the Program was $6.5 million in direct costs from the NCI and $2.6 million from other sponsors. During the current funding period, primary Program members published 1,004 cancer-relevant papers. Of these, 27% were inter-institutional, 27% were intra-programmatic, and 42% were inter-programmatic collaborations between two or more DF/HCC members. To achieve the Program mission, we propose the following Specific Aims during the next CCSG funding period: 1) Identify environmental, social, and genomic determinants of lung cancer risk and their role in susceptibility, pathogenesis, and prognosis of lung cancer; 2) Define pathogenic mechanisms that underlie the development and evolution of lung cancer; 3) Exploit the discoveries in cell biology to characterize signaling pathway activated by driver oncogenes to develop novel therapeutic approaches to thoracic malignancies; 4) Characterize the mechanisms of primary and acquired resistance to targeted