RRC ID 57746
Author Behan FM, Iorio F, Picco G, Gonçalves E, Beaver CM, Migliardi G, Santos R, Rao Y, Sassi F, Pinnelli M, Ansari R, Harper S, Jackson DA, McRae R, Pooley R, Wilkinson P, van der Meer D, Dow D, Buser-Doepner C, Bertotti A, Trusolino L, Stronach EA, Saez-Rodriguez J, Yusa K, Garnett MJ.
Title Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.
Journal Nature
Abstract Functional genomics approaches can overcome limitations-such as the lack of identification of robust targets and poor clinical efficacy-that hamper cancer drug development. Here we performed genome-scale CRISPR-Cas9 screens in 324 human cancer cell lines from 30 cancer types and developed a data-driven framework to prioritize candidates for cancer therapeutics. We integrated cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritize new targets in defined tissues and genotypes. We verified one of our most promising dependencies, the Werner syndrome ATP-dependent helicase, as a synthetic lethal target in tumours from multiple cancer types with microsatellite instability. Our analysis provides a resource of cancer dependencies, generates a framework to prioritize cancer drug targets and suggests specific new targets. The principles described in this study can inform the initial stages of drug development by contributing to a new, diverse and more effective portfolio of cancer drug targets.
Volume 568(7753)
Pages 511-516
Published 2019-4-1
DOI 10.1038/s41586-019-1103-9
PII 10.1038/s41586-019-1103-9
PMID 30971826
MeSH Animals Biomarkers, Tumor / genetics CRISPR-Cas Systems / genetics* Cell Line, Tumor Drug Discovery / methods* Female Gene Editing* Genome, Human / genetics Humans Mice Microsatellite Instability Molecular Targeted Therapy / methods* Neoplasm Transplantation Neoplasms / classification Neoplasms / genetics* Neoplasms / pathology Neoplasms / therapy* Organ Specificity Reproducibility of Results Synthetic Lethal Mutations / genetics Werner Syndrome / genetics Werner Syndrome Helicase / genetics
IF 42.779
Times Cited 111
Human and Animal Cells Ca9-22(RCB1976) OVK18(RCB1903) OCUB-M(RCB0881) NB69(RCB0480) TE-15(RCB1951) TE-4(RCB2097) TGBC11TKB(RCB1148) MKN1(RCB1003) MDA-MB-453(RCB1192) GI-1(RCB0763) GCIY(RCB0555) EC-GI-10(RCB0774) HGC-27(RCB0500) LC-1/sq(RCB0455) KP4(RCB1005) JHOS-4(RCB1678) JHOS-2(RCB1521)