TAS-115 inhibits PDGFRα/AXL/FLT-3 signaling and suppresses lung metastasis of osteosarcoma

FEBS Open Bio. 2020 May;10(5):767-779. doi: 10.1002/2211-5463.12827. Epub 2020 Mar 30.

Abstract

Osteosarcoma is the most common malignant bone tumor in adolescence and childhood. Metastatic osteosarcoma has a poor prognosis with an overall 5-year survival rate of approximately 20%. TAS-115 is a novel multiple receptor tyrosine kinase inhibitor that is currently undergoing clinical trials. Using the mouse highly lung-metastatic osteosarcoma cell line, LM8, we showed that TAS-115 suppressed the growth of subcutaneous grafted tumor and lung metastasis of osteosarcoma at least partially through the inhibition of platelet-derived growth factor receptor alpha, AXL, and Fms-like tyrosine kinase 3 phosphorylation. We also show that these signaling pathways are activated in various human osteosarcoma cell lines and are involved in proliferation. Our results suggest that TAS-115 may have potential for development into a novel treatment for metastatic osteosarcoma.

Keywords: LM8; TAS-115; lung metastasis; molecular targeted therapy; osteosarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axl Receptor Tyrosine Kinase
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Female
  • Humans
  • Lung Neoplasms
  • Mice
  • Mice, Inbred C3H
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / metabolism
  • Quinolines / metabolism
  • Quinolines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor Protein-Tyrosine Kinases / physiology
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / physiology
  • Signal Transduction / drug effects
  • Thiourea / analogs & derivatives*
  • Thiourea / metabolism
  • Thiourea / pharmacology
  • fms-Like Tyrosine Kinase 3 / metabolism
  • fms-Like Tyrosine Kinase 3 / physiology

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Quinolines
  • Proto-Oncogene Proteins c-met
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor alpha
  • fms-Like Tyrosine Kinase 3
  • Proto-Oncogene Proteins c-akt
  • Thiourea
  • 4-(2-fluoro-4-((((2-phenylacetyl)amino)thioxomethyl)amino)phenoxy)-7-methoxy-N-methyl-6-quinolinecarboxamide
  • Axl Receptor Tyrosine Kinase