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 Meer, David Dow, Carolyn Buser-Doepner, Andrea Bertotti, Livio Trusolino, Euan A. Stronach, Julio Saez-Rodriguez, Kosuke Yusa () and Mathew J. Garnett ()
Additional contact information
Fiona M. Behan: Wellcome Sanger Institute
Francesco Iorio: Wellcome Sanger Institute
Gabriele Picco: Wellcome Sanger Institute
Emanuel Gonçalves: Wellcome Sanger Institute
Charlotte M. Beaver: Wellcome Sanger Institute
Giorgia Migliardi: Candiolo Cancer Institute-FPO, IRCCS
Rita Santos: GlaxoSmithKline Research and Development
Yanhua Rao: GlaxoSmithKline Research and Development
Francesco Sassi: Candiolo Cancer Institute-FPO, IRCCS
Marika Pinnelli: Candiolo Cancer Institute-FPO, IRCCS
Rizwan Ansari: Wellcome Sanger Institute
Sarah Harper: Wellcome Sanger Institute
David Adam Jackson: Wellcome Sanger Institute
Rebecca McRae: Wellcome Sanger Institute
Rachel Pooley: Wellcome Sanger Institute
Piers Wilkinson: Wellcome Sanger Institute
Dieudonne Meer: Wellcome Sanger Institute
David Dow: Open Targets
Carolyn Buser-Doepner: Open Targets
Andrea Bertotti: Candiolo Cancer Institute-FPO, IRCCS
Livio Trusolino: Candiolo Cancer Institute-FPO, IRCCS
Euan A. Stronach: Open Targets
Julio Saez-Rodriguez: Open Targets
Kosuke Yusa: Wellcome Sanger Institute
Mathew J. Garnett: Wellcome Sanger Institute

Nature, 2019, vol. 568, issue 7753, 511-516

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1103-9

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