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Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens

Fiona M Behan1,2, Francesco Iorio1,2,3, Gabriele Picco1

  • 1Wellcome Sanger Institute, Cambridge, UK.

Nature
|April 12, 2019
PubMed

Insights

This study used CRISPR-Cas9 screens across 324 cancer cell lines to identify new therapeutic targets. A key finding is the Werner syndrome helicase as a synthetic lethal target in microsatellite unstable tumors, advancing cancer drug development.

Area of Science:

  • Genomics
  • Cancer Biology
  • Drug Discovery

Background:

  • Cancer drug development faces challenges with target identification and clinical efficacy.
  • Functional genomics offers a path to overcome these limitations.

Purpose of the Study:

  • To perform genome-scale CRISPR-Cas9 screens in a large cohort of human cancer cell lines.
  • To develop a data-driven framework for prioritizing cancer therapeutic targets.
  • To identify novel, druggable targets for diverse cancer types and genotypes.

Main Methods:

  • Genome-scale CRISPR-Cas9 screening in 324 human cancer cell lines across 30 cancer types.
  • Integration of cell fitness data with genomic biomarkers and target tractability.
  • Prioritization of potential drug targets based on integrated data.

Main Results:

  • Identification of numerous cancer-specific dependencies.
  • Development of a framework for systematic target prioritization.
  • Validation of Werner syndrome ATP-dependent helicase as a synthetic lethal target in microsatellite unstable tumors.

Conclusions:

  • The study provides a valuable resource of cancer dependencies and a framework for target discovery.
  • Werner syndrome helicase is a promising synthetic lethal target for specific cancer types.
  • This approach can contribute to a more diverse and effective pipeline of cancer therapeutics.

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