Cited by 1,338CRISPR and Genetic EngineeringChromatin Remodeling and CancerCancer Genomics and Diagnostics

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Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens

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Behan, Fiona M., Iorio, Francesco, Picco, Gabriele, Gonçalves, Emanuel, Beaver, Charlotte M., Migliardi, Giorgia, Santos, Rita, Rao, Yanhua, Sassi, Francesco, Pinnelli, Marika, Ansari, Rizwan, Harper, Sarah, Jackson, David Adam, McRae, Rebecca, Pooley, Rachel, Wilkinson, Piers, van der Meer, Dieudonne, Dow, David, Buser-Doepner, Carolyn, Bertotti, Andrea, Trusolino, Livio, Stronach, Euan A., Saez-Rodriguez, Julio, Yusa, Kosuke, Garnett, Mathew J.·2019·Nature

DOI 10.1038/s41586-019-1103-9

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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.

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Self-citation

Authors: Behan, F. M., Iorio, F., Picco, G., Gonçalves, E., Beaver, C. M., Migliardi, G., Santos, R., Rao, Y., Sassi, F., Pinnelli, M., Ansari, R., Harper, S., Jackson, D. A., McRae, R., Pooley, R., Wilkinson, P., van der Meer, D., Dow, D., Buser-Doepner, C., Bertotti, A., Trusolino, L., Stronach, E. A., Saez-Rodriguez, J., Yusa, K., & Garnett, M. J.
Affiliations: Wellcome Sanger Institute (GB)
European Bioinformatics Institute (GB)
Candiolo Cancer Institute (IT)
GlaxoSmithKline (United Kingdom) (GB)
GlaxoSmithKline (United States) (US)
Kyoto University (JP)
Corresponding author: Yusa, Kosuke
Garnett, Mathew J.
ORCID: Behan, Fiona M.
Iorio, Francesco
Picco, Gabriele
Gonçalves, Emanuel
Migliardi, Giorgia
Santos, Rita
Rao, Yanhua
Sassi, Francesco
Pinnelli, Marika
Ansari, Rizwan
Pooley, Rachel
Wilkinson, Piers
Bertotti, Andrea
Trusolino, Livio
Stronach, Euan A.
Yusa, Kosuke
Garnett, Mathew J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-04-10
Volume: 568
Issue: 7753
Pages: 511-516
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-1103-9
OpenAlex: W2936686072
Cited by: 1,338
References: 64
Citations by year: 2026: 129 · 2025: 168 · 2024: 200 · 2023: 158 · 2022: 200 · 2021: 227 · 2020: 179 · 2019: 74
FWCI: 56.69
Type: journal article
Language: en
Open access: green
doi.org
Licence: cc-by-nc-nd
www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
RePEc: Research Papers in Economics (submittedVersion)
RWTH Publications (RWTH Aachen) (submittedVersion)
Funders: Wellcome Trust (C44943/A22536, SU2C-AACR-DT1213, 102696, 206194)
Cancer Research UK (A22536, SU2C-AACR-DT1213, 102696, C44943/A22536)
Associazione Italiana per la Ricerca sul Cancro (5X 1000, 21091, 20697, 18532)
Stand Up To Cancer (SU2C-AACRDT1213)
H2020 European Research Council (724748)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: cancer cell lines, synthetic lethality, microsatellite instability, cancer dependency, genomic biomarkers, anticancer drug development
MeSH terms: Werner Syndrome Helicase, Synthetic Lethal Mutations, Gene Editing, Animals, Female, Humans, Neoplasm Transplantation, Neoplasms, Organ Specificity, Biomarkers, Tumor, Werner Syndrome, Reproducibility of Results, Genome, Human, Cell Line, Tumor, Mice, Microsatellite Instability, Drug Discovery, Molecular Targeted Therapy, CRISPR-Cas Systems

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