Abstract B10: Synthetic lethal screen to identify novel therapies targeting TP53-mutant colon cancer cells

Abstract

Abstract We have performed a genome-wide synthetic lethal screen for pathways that are essential for the survival of colon cancer cells with TP53 mutations. RKO colon cancer cells are wild-type for TP53, and display robust p53-dependent growth arrest and apoptosis. We have utilized an isogenic pair of RKO cells differing only in TP53 gene status (Wild Type vs homozygous null derivative) to screen a genome-wide GeCKO CRISPR library and identified pathways that are novel therapeutic targets for TP53-mutant colon cancers. After infection of these cells with the GeCKO CRISPR library and one week of culturing in vitro, we performed deep GeCKO CRIPSR amplicon sequencing to enumerate and identify all CRISPRs that were underrepresented in TP53 mutant compared to wild type cells. We identified multiple CRISPRs targeting the CHEK1 and the SHH genes which were underrepresented in TP53 knockout cells. We then tested small molecule inhibitors of CHEK1 (UCN01) and the SHH receptor SMO (Cyclopamine) against isogenic pairs of RKO, HCT116, and DLD1 cells and confirmed that each molecule is significantly more toxic to cells with mutant TP53 than to those with wild-type TP53. Future studies will focus on testing these and additional targets alone and in combination against primary colon tumor and normal avatars, and preclinical models of TP53-mutant colon cancer. Citation Format: Charles C. Weige, Erin L. Anderson, Joseph Richardson, Carlo Contreras, Phillip J. Buckhaults. Synthetic lethal screen to identify novel therapies targeting TP53-mutant colon cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B10.