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Published on: July 3, 2013
Genome-Wide CRISPR Screen for Essential Cell Growth Mediators in Mutant KRAS Colorectal Cancers
Edwin H Yau1,2,3, Indrasena Reddy Kummetha1, Gianluigi Lichinchi1
1Department of Pediatrics and Institute for Genomic Medicine, University of California San Diego School of Medicine, La Jolla, California.
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 (KRASMUT) 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 KRASMUT colorectal cancer, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase or ketohexokinase was growth inhibitory in vivo In addition, 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 Res; 77(22); 6330-9. ©2017 AACR.
Insights
Researchers used CRISPR-Cas9 to find new therapeutic targets for mutant KRAS colorectal cancers. Inhibiting specific metabolic enzymes and the INO80C protein showed promise for treating these aggressive tumors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Targeting mutant KRAS (KRASMUT) signaling is a key strategy for KRAS-driven tumors.
- Identifying novel genes that influence KRASMUT tumor growth is crucial for developing new therapies.
Purpose of the Study:
- To identify genes that, when lost, affect the tumor xenograft growth of human mutant KRAS colorectal cancers.
- To discover novel synthetic enhancers or synthetic lethals for KRASMUT colorectal cancer.
Main Methods:
- Utilized the CRISPR-Cas9 system for genome-wide loss-of-function genetic screening.
- Employed pooled lentiviral single-guide RNA libraries in an isogenic pair of human colorectal cancer cell lines (mutant vs. wild-type KRAS).
Main Results:
- Identified novel and known synthetic enhancers and lethals for KRASMUT colorectal cancer.
- Disruption or inhibition of metabolic enzymes NAD kinase and ketohexokinase demonstrated in vivo growth inhibition.
- INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts.
Conclusions:
- Defined a set of novel, targetable therapeutic targets for KRASMUT tumors.
- Findings provide a foundation for developing new treatment strategies for KRAS-driven cancers.
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