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

Naohiro Yasuda; Satoshi Takenaka; Sho Nakai; Takaaki Nakai; Shutaro Yamada; Yoshinori Imura; Hidetatsu Outani; Kenichiro Hamada; Hideki Yoshikawa; Norifumi Naka

doi:10.1002/2211-5463.12827

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.

Authors

Affiliations

¹ Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
² Department of Orthopaedic Surgery, Kawachi General Hospital, Higashiosaka, Japan.
³ Department of Orthopaedic Surgery, Yao Municipal Hospital, Japan.
⁴ Musculoskeletal Oncology Service, Osaka International Cancer Institute, Japan.
⁵ Department of Orthopaedic Surgery, Toyonaka Municipal Hospital, Japan.

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