Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.

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 Organ Specificity Reproducibility of Results Synthetic Lethal Mutations / genetics Werner Syndrome / genetics Werner Syndrome Helicase / genetics

Journal

Nature

ISSN: 1476-4687

Titre abrégé: Nature

Pays: England

ID NLM: 0410462

Informations de publication

Date de publication:
04 2019

Historique:

received: 03 08 2018

accepted: 08 03 2019

pubmed: 12 4 2019

medline: 18 12 2019

entrez: 12 4 2019

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41586-019-1103-9 PMID: 30971826

pubmed: 30971826

doi: 10.1038/s41586-019-1103-9

pii: 10.1038/s41586-019-1103-9

doi:

Substances chimiques

Biomarkers, Tumor 0

Werner Syndrome Helicase EC 3.6.4.12

Types de publication

Journal Article Validation Study

Langues

eng

Sous-ensembles de citation

Pagination

511-516

Commentaires et corrections

Type : CommentIn

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