This application addresses the FY18 PRCRP topic area of Colorectal Cancer. Military relevant risk factors such as ionizing radiation often produce cancers with mutations in TP53. This proposal seeks to address a gap in colorectal cancer treatment that has profound impact on the health and well-being of military service Veterans, their beneficiaries, and extends to the American public as a whole. TP53 mutations are common in colon cancers (50%), and most often lead to resistance to chemotherapy. A systematic screen for synthetic lethal interactions between gene knockout, TP53 mutation, and chemotherapy such as Cisplatin will produce novel targets useful for treating a large fraction of colon cancers.