A comprehensive clinically informed map of dependencies in cancer cells and framework for target prioritization

Cancer Cell. 2024 Feb 12;42(2):301-316.e9. doi: 10.1016/j.ccell.2023.12.016. Epub 2024 Jan 11.

Abstract

Genetic screens in cancer cell lines inform gene function and drug discovery. More comprehensive screen datasets with multi-omics data are needed to enhance opportunities to functionally map genetic vulnerabilities. Here, we construct a second-generation map of cancer dependencies by annotating 930 cancer cell lines with multi-omic data and analyze relationships between molecular markers and cancer dependencies derived from CRISPR-Cas9 screens. We identify dependency-associated gene expression markers beyond driver genes, and observe many gene addiction relationships driven by gain of function rather than synthetic lethal effects. By combining clinically informed dependency-marker associations with protein-protein interaction networks, we identify 370 anti-cancer priority targets for 27 cancer types, many of which have network-based evidence of a functional link with a marker in a cancer type. Mapping these targets to sequenced tumor cohorts identifies tractable targets in different cancer types. This target prioritization map enhances understanding of gene dependencies and identifies candidate anti-cancer targets for drug development.

Keywords: CRISPR; Cancer; biomarker; cell lines; drug discovery; gene dependencies; genomics; protein interactions; target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Drug Discovery
  • Genetic Testing*
  • Humans
  • Neoplasms* / genetics
  • Neoplasms* / pathology
  • Phenotype