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

Cancer Res. 2017 Nov 15;77(22):6330-6339. doi: 10.1158/0008-5472.CAN-17-2043. Epub 2017 Sep 27.

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.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • CRISPR-Cas Systems*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics*
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Helicases / genetics
  • DNA-Binding Proteins
  • Fructokinases / genetics
  • Genome-Wide Association Study / methods*
  • HCT116 Cells
  • Humans
  • Mutation*
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Protein Subunits / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Xenograft Model Antitumor Assays / methods

Substances

  • DNA-Binding Proteins
  • KRAS protein, human
  • Protein Subunits
  • Niacinamide
  • thionicotinamide
  • Fructokinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • NAD kinase
  • ketohexokinase
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • INO80 protein, human
  • Proto-Oncogene Proteins p21(ras)