The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

Nat Commun. 2015 Apr 30;6:7002. doi: 10.1038/ncomms8002.

Abstract

The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Cell Line, Tumor
  • Cetuximab
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • ErbB Receptors / antagonists & inhibitors*
  • Genes, erbB-1
  • Genetic Heterogeneity
  • Humans
  • Molecular Targeted Therapy
  • Proto-Oncogene Proteins c-ret / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism

Substances

  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • ErbB Receptors
  • FGFR2 protein, human
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 2
  • Cetuximab

Associated data

  • GEO/GSE59857