Genome-Wide CRISPR Screen for Essential Cell Growth Mediators in Mutant KRAS Colorectal Cancers

Abstract

Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS (KRAS^MUT) colorectal cancers. Using pooled lentiviral single-guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human colorectal cancer cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRAS^MUT colorectal cancer, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase or ketohexokinase was growth inhibitory <i>in vivo</i> In addition, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRAS^MUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRAS^MUT tumors. <i>Cancer Res; 77(22); 6330-9. ©2017 AACR</i>.