Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens
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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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MSI that often leads to cancer simultaneously makes the inhibition of WRN lethal to tumor cells.
“the MSI that often leads to cancer simultaneously makes the inhibition of Werner syndrome ATP-dependent helicase (WRN) lethal to the tumor cells62,63”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [62]
Fitness Scores calculated from large-scale genome-wide CRISPR/Cas9 screens across 31 independent CRC cell lines represent a quantitative measure of the reduction of cell viability elicited by gene inactivation via CRISPR/Cas9.
“''Fitness Scores'' that were calculated from large-scale genome-wide CRISPR/Cas9 screens across 31 independent CRC cell lines and represent a quantitative measure of the reduction of cell viability elicited by a gene inactivation via CRISPR/Cas9 (https://score.depmap.sanger.ac.uk) (Behan et al., 2019;van der Meer et al., 2019).”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Behan et al., 2019
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Gong, S., Zhang, S., Lü, F., Pan, W., Li, N., & Tang, B. (2021) · Analytical Chemistry · doi:10.1021/acs.analchem.1c02533 · Cited by 99 · see citing works
- 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
- Venue
- Nature
- Published
- 2019-04-10
- Volume
- 568
- Issue
- 7753
- Pages
- 511-516
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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 · 2018: 2 · 2012: 1
- FWCI
- 56.69
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- 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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