PROJECT SUMMARY Large-scale genomic surveys of lung adenocarcinoma have revealed frequent mutations in the RNA-binding protein RBM10. RBM10 mutations consist mainly of loss-of-function alterations, suggesting it may function as a tumor suppressor gene. The main goals of this proposal are to investigate the role of RBM10 mutations in lung tumorigenesis and to identify potential genetic dependencies specific to RBM10-deficient lung cancer cells. In Aim 1, Rbm10 will be targeted directly in the mouse lung to assess the effects of Rbm10 loss-of-function in a model of mutant KrasG12D-induced lung adenocarcinoma. In Aim 2, RNA transcripts that interact with RBM10 in lung cancer cells will be identified along with exons that are differentially spliced in the presence or absence of RBM10. For each of the approaches in Aim 2, both human and mouse cancer cells will be studied, providing a unique and powerful set of data for identifying the most conserved and functionally relevant targets of RBM10. Finally, in Aim 3, a genome-wide CRISPR/Cas9 knockout screen will be carried out to find unique vulnerabilities in RBM10 mutant cells. The proposed research plan will improve our understanding of how disruptions to normal RNA splicing can contribute to human cancer and may yield novel therapeutic targets. Dr. Peter Choi is currently a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at the Dana-Farber Cancer Institute and Broad Institute. His long-term goal is to lead an independent research group in the study of how genetic alterations are functionally responsible for human cancer. He will carry out his research during the K99 period under the primary mentorship of Dr. Meyerson, who is a leader in lung cancer genomics. Additional mentorship will be provided by an advisory committee consisting of Drs. Hahn, Barbie, Hammerman, and Harlow who will monitor Dr. Choi's scientific progress and career development, as well as help guide his transition to a tenure-track faculty position.