Abstract IA06: Leveraging genome-wide CRISPR screens and synthetic lethal interactions for novel cancer therapeutics

Abstract

Abstract Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43 mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation, and discovered a unique requirement for a Wnt signaling circuit engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context dependent specificity at the Wnt receptor level. We further derived a panel of recombinant antibodies that reports the expression of nine FZD proteins and confirm that FZD5 functional specificity cannot be explained by protein expression patterns. Antibodies that specifically bind FZD5 and FZD8 also robustly inhibited the growth of RNF43 mutant PDAC cells grown in vitro and as xenografts in vivo, providing strong orthogonal support for the functional specificity observed genetically. Proliferation of a patient-derived PDAC cell line harboring a RNF43 variant previously associated with PDAC was also selectively inhibited by the FZD5 antibodies, further demonstrating their use as a potential targeted therapy. Highlighting the potential generalizability of these findings, beyond PDAC, tumor organoid cultures from colorectal carcinoma patients that carried RNF43 mutations were also sensitive to the FZD5 antibodies. Our results provide the first example of how CRIPSR-based genetic screens can be leveraged to identify and validate cell surface targets for antibody development and cancer therapy. Citation Format: Stephane Angers. Leveraging genome-wide CRISPR screens and synthetic lethal interactions for novel cancer therapeutics [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA06.