Fibroblast growth factor receptors as novel therapeutic targets in SNF5-deleted malignant rhabdoid tumors

PLoS One. 2013 Oct 30;8(10):e77652. doi: 10.1371/journal.pone.0077652. eCollection 2013.

Abstract

Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin Assembly and Disassembly / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Promoter Regions, Genetic / genetics
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Rhabdoid Tumor / genetics
  • Rhabdoid Tumor / metabolism*
  • SMARCB1 Protein
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Receptors, Fibroblast Growth Factor
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors