A first-generation pediatric cancer dependency map

Nat Genet. 2021 Apr;53(4):529-538. doi: 10.1038/s41588-021-00819-w. Epub 2021 Mar 22.

Abstract

Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were subjected to genome-scale CRISPR-Cas9 loss-of-function screening to identify genes required for cell survival. In contrast to the finding that pediatric cancers harbor fewer somatic mutations, we found a similar complexity of genetic dependencies in pediatric cancer cell lines compared to that in adult models. Findings from the pediatric cancer dependency map provide preclinical support for ongoing precision medicine clinical trials. The vulnerabilities observed in pediatric cancers were often distinct from those in adult cancer, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • CRISPR-Associated Protein 9 / genetics
  • CRISPR-Associated Protein 9 / metabolism
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Child
  • Chromosome Mapping / methods*
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Gene Editing
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genetic Predisposition to Disease
  • Genome, Human*
  • Humans
  • Mutation*
  • Neoplasm Proteins / classification
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • RNA, Guide / genetics
  • RNA, Guide / metabolism

Substances

  • Neoplasm Proteins
  • RNA, Guide
  • CRISPR-Associated Protein 9