Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma

Oncotarget. 2016 Aug 23;7(34):54583-54595. doi: 10.18632/oncotarget.10518.

Abstract

Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines. We have analyzed three metastases from a patient with high-grade metastatic dedifferentiated liposarcoma (DDLPS) by exome and transcriptome sequencing as well as DNA copy number analysis. Genomic aberrations of several potentially targetable genes, including amplification of KITLG and FRS2, in addition to amplification of CDK4 and MDM2, characteristic of this disease, were identified. We evaluated the efficacy of drugs targeting these aberrations or the corresponding signaling pathways in a cell line derived from the patient. Interestingly, the pan-FGFR inhibitor NVP-BGJ398, which targets FGFR upstream of FRS2, strongly inhibited cell proliferation in vitro and induced an accumulation of cells into the G0 phase of the cell cycle. This study indicates that FGFR inhibitors have therapeutic potential in the treatment of DDLPS with amplified FRS2.

Keywords: FRS2; NVP-BGJ398; liposarcoma; personalized genomics; targeted therapy.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Gene Dosage
  • Humans
  • Liposarcoma / drug therapy*
  • Liposarcoma / genetics
  • Liposarcoma / pathology
  • Membrane Proteins / genetics
  • Mice
  • Polymorphism, Single Nucleotide
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Sequence Analysis, RNA
  • Stem Cell Factor / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • FRS2 protein, human
  • Membrane Proteins
  • Receptors, Fibroblast Growth Factor
  • Stem Cell Factor
  • Cyclin-Dependent Kinase 4