Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Cancer Cell. 2016 Dec 12;30(6):891-908. doi: 10.1016/j.ccell.2016.11.003.

Abstract

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Keywords: ATRT; enhancer; epigenomics; genomics; rhabdoid tumors; subgroup-specific therapeutics.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Central Nervous System Neoplasms / drug therapy
  • Central Nervous System Neoplasms / genetics*
  • Chromatin / genetics*
  • DNA Methylation
  • Dasatinib / pharmacology
  • Dasatinib / therapeutic use
  • Epigenesis, Genetic / drug effects
  • Epigenomics / methods*
  • Humans
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor beta / genetics*
  • Rhabdoid Tumor / drug therapy
  • Rhabdoid Tumor / genetics*
  • SMARCB1 Protein / genetics*
  • Teratoma / drug therapy
  • Teratoma / genetics*

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Chromatin
  • Protein Kinase Inhibitors
  • Pyrimidines
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • PDGFRB protein, human
  • Receptor, Platelet-Derived Growth Factor beta
  • Dasatinib

Supplementary concepts

  • Typical Teratoid Rhabdoid Tumor