Abstract
Abstract The MYC oncogene is frequently overexpressed in human cancers. However, targeting MYC directly has proven to be extremely difficult and MYC itself is currently considered undruggable. We sought to identify alternative genetic vulnerabilities of MYC-driven cancer by using CRISPR-based genome-wide synthetic lethality screens. The library screens were performed in a MYC-driven cancer cell line derived from our transgenic mouse model of hepatocellular carcinoma. In this cancer cell line, the level of MYC is regulated by the Tet-Off transgenic system. Using lentiviral infection, the Cas9 nuclease was delivered into the cells, followed by the CRISPR library with 130,000 guide RNAs to knock out each gene in the mouse genome. Comparison of the clonal dropouts under high MYC versus low MYC conditions lead to the identification of specific target genes that are essential to tumors with high MYC expression. Preliminary pathway analysis of our screening hits has revealed the functional landscape of the MYC oncogene. We found that several pathways that are essential for MYC function converge on RNA metabolism. Furthermore, we have identified and tested druggable targets that can be translated into therapeutics for MYC-driven cancers. Citation Format: Yulin Li, Anja Deutzmann, John Bell, Hanlee Ji, Dean Felsher. Synthetic lethality screen identifies novel druggable targets in the MYC pathway [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 PR02.
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