Genome-wide CRISPR screen for essential cell growth mediators in mutant KRAS colorectal cancers
Menée à l'aide de la technologie CRISPR-Cas9 et de xénogreffes de lignées cellulaires humaines de cancer colorectal présentant un gène KRAS muté, cette étude identifie notamment deux enzymes (NADK et KHK) favorisant la croissance tumorale et une protéine impliquée dans le remodelage de la chromatine (INO80C) exerçant une fonction de suppresseur de tumeurs
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 colorectal cancers (KRASMUT CRC). Using pooled lentiviral single guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human CRC cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRASMUT CRC, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase (NADK) or ketohexokinase (KHK) were growth inhibitory in vivo. Additionally, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRASMUT tumors.
Cancer Research 2017