Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens

Fiona M. Behan, Francesco Iorio, Gabriele Picco, Emanuel Gonçalves, Charlotte M. Beaver, Giorgia Migliardi, Rita Santos, Yanhua Rao, Francesco Sassi, Marika Pinnelli, Rizwan Ansari, Sarah Harper, David Adam Jackson, Rebecca McRae, Rachel Pooley, Piers Wilkinson, Dieudonne van der Meer, David Dow, Carolyn Buser-Doepner, Andrea BertottiLivio Trusolino, Euan A. Stronach, Julio Saez-Rodriguez, Kosuke Yusa, Mathew J. Garnett

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)511-516
Number of pages6
JournalNature
Volume568
Issue number7753
DOIs
Publication statusPublished - Apr 25 2019

ASJC Scopus subject areas

  • General

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