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Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma

Robert Hanes1,2, Else Munthe3, Iwona Grad4

  • 1Department of Tumor Biology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway. Robert.Hanes@rr-research.no.

Cells
|February 24, 2019
PubMed

Insights

A potent FGFR inhibitor, LY2874455, shows promise for treating dedifferentiated liposarcoma (DDLPS) with FRS2 amplification, demonstrating significant growth inhibition and apoptosis in vivo. Further clinical trials are warranted for this improved therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Fibroblast Growth Factor Receptor (FGFR) inhibition is a potential therapeutic strategy for dedifferentiated liposarcoma (DDLPS) with FRS2 amplification.
  • Previous studies using NVP-BGJ398 showed only transient cytostatic effects in FRS2-amplified DDLPS cells.

Purpose of the Study:

  • To evaluate the efficacy of a more potent FGFR inhibitor, LY2874455, in FRS2-amplified DDLPS.
  • To investigate the mechanisms underlying response and non-response to FGFR inhibition in DDLPS.

Main Methods:

  • Assessed the effects of LY2874455 on cell growth and apoptosis in three DDLPS cell lines in vitro.
  • Evaluated LY2874455 efficacy in an FRS2-amplified DDLPS xenograft model in vivo.
  • Performed genome, transcriptome, and protein analyses to characterize FGFR pathway signaling components.

Main Results:

  • LY2874455 demonstrated stronger, sustained growth inhibition and moderate apoptosis in two of three DDLPS cell lines.
  • One cell line did not respond to LY2874455, indicating FRS2 amplification alone is insufficient for predicting response.
  • LY2874455 efficacy was confirmed in vivo in an independent FRS2-amplified DDLPS xenograft model. Responding cells expressed FGF2, while non-responding cells expressed FGF11.

Conclusions:

  • LY2874455 is a more effective FGFR inhibitor than NVP-BGJ398 for FRS2-amplified liposarcoma.
  • The study supports the potential of LY2874455 as a therapeutic agent for FRS2-amplified liposarcoma.
  • A clinical trial investigating LY2874455 for DDLPS is warranted.
Keywords:
FGFRFRS2LY2874455NVP-BGJ398sarcoma

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