Project Summary/Abstract Since biologic events underlie clinical outcomes, we hypothesize that unraveling mechanisms of intracellular signaling and metastasis in lung cancers will lead to the identification of new targets for therapy for these illnesses and for individual patients. Our experience developing EGFR and ALK kinase inhibitors, and the discoveries that mutations in EGFR and KRAS and ALK- rearrangements underlie sensitivity and resistance to targeted therapies, have shown the practicality and potential of this approach. Our 4 research projects and 3 cores propose to continue a decade long iterative research process uniting clinical and laboratory observations. These efforts have linked genetic aberrations in tumors to outcomes in patients and identified agents targeting these same aberrations that benefit persons with lung cancers. This grant embraces investigators, technologies, and pathways, each focused by specific clinical questions, proposing to identify targets for therapies in lung cancers. Project 1 (Massagué) identifies mediators of metastasis and immune evasion that can serve as targets for intervention. Project 2 (Rosen) probes signaling in BRAF- and KRAS-driven lung cancers. Project 3 (Lovely) investigates mechanisms and modulators of sensitivity and resistance to EGFR and ALK kinase inhibitors. Project 4 (Lowe) uses mouse models and RNA interference to interrogate KRAS- driven lung cancers focusing on combinatorial strategies including the allele specific inhibitors studied in Project 2 and probing the impact of therapy-induced senescence on immune surveillance. Our Molecular Profiling and Pathology Core crystallizes more than a decade of experience in precise pathologic characterization, and use of the next-generation technologies for comprehensive molecular profiling of lung cancers. The Biostatistics and Bioinformatics Core ensures consistency in biostatistical analyses and provides projects and the Pathology Core with analytic capabilities for genomic data. The Administrative Core has created an organizational structure that assures integration and interaction by facilitating communication and dissemination of findings and providing a forum for the principal investigators, leaders, and the Executive and Scientific Advisory Committees to conduct scientific review and integration of new opportunities to accelerate progress.