ABSTRACT RAS signaling is one of the most commonly altered oncogenic pathways in human cancer and one of the most targeted pathways in drug discovery programs. Yet, while numerous small molecule inhibitors of RAS effectors have been identified, the importance of RAS/MAPK signaling in normal tissues and numerous compensatory signaling mechanisms engaged by cancer cells have prevented their therapeutic utility in many cases. Identifying new therapeutic targets may help overcome the limitations associated with current precision therapies. The goal of this proposal is to define the role of the novel oncogene FAM83B, an important RAS/MAPK intermediary, in driving lung hyperplasia and cancer development in vivo using a newly developed FAM83B mouse model. We originally identified FAM83B in a forward genetic screen for genes that drive human epithelial cell transformation, similar to mutant RAS. Our analysis of FAM83B has generated extensive new information about the molecular functions of FAM83B in cancer cells. We found that elevated FAM83B expression increases RAS/MAPK signaling, resulting in resistance to a number of targeted therapies. Importantly, inhibition of FAM83B suppresses RAS/MAPK signaling and reduces tumor growth. FAM83B is significantly elevated in many cancers, including lung cancer, where it is now recognized as a biomarker in patients with lung adenocarcinoma that have poor outcomes. Here, we propose to use our innovative new FAM83B mouse model to assess how FAM83B contributes to lung tumorigenesis in vivo. The objectives of the proposed studies are to: (i) define the role of FAM83B in driving lung cancer in vivo, alone or in the presence of mutant KRAS, and (ii) determine the FAM83B- dependent molecular changes in MAPK pathway activation responsible for driving tumorigenesis. While the proposed studies focus on FAM83B, the impact of our studies is expected to be considerably broader. A second FAM83 member, FAM83A, was also identified in a forward genetics screen for genes conferring resistance to EGFR TKIs in transformed HMEC. Importantly, FAM83A and FAM83B are members of an 8 member protein family, with all FAM83 proteins now shown to activate MAPK signaling in cancer cell lines (via a highly conserved domain) thereby contributing to tumorigenesis. Thus, our findings using the innovative FAM83B mouse model to assess how FAM83B contributes to MAPK activation and tumorigenesis in vivo will also inform research into all FAM83 members, across numerous cancer types.