Cabozantinib inhibits AXL- and MET-dependent cancer cell migration induced by growth-arrest-specific 6 and hepatocyte growth factor

Takahito Hara; Akiko Kimura; Tohru Miyazaki; Hiroshi Tanaka; Megumi Morimoto; Katsuhiko Nakai; Junpei Soeda

doi:10.1016/j.bbrep.2020.100726

Cabozantinib inhibits AXL- and MET-dependent cancer cell migration induced by growth-arrest-specific 6 and hepatocyte growth factor

Biochem Biophys Rep. 2020 Jan 17:21:100726. doi: 10.1016/j.bbrep.2020.100726. eCollection 2020 Mar.

Authors

Takahito Hara¹, Akiko Kimura², Tohru Miyazaki³, Hiroshi Tanaka⁴, Megumi Morimoto¹, Katsuhiko Nakai², Junpei Soeda³

Affiliations

¹ Innovation Promotion, Shonan Research Central Office, Research, Takeda Pharmaceutical Company Limited, 2-26-1 Muraoka-Higashi, Fujisawa-shi, Kanagawa, 251-8555, Japan.
² Oncology Therapeutic Area Unit for Japan & Asia, Takeda Pharmaceutical Company Limited, 4-1-1 Dosho-machi Chuo-ku Osaka-shi, Osaka, 540-8645, Japan.
³ Department of Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Limited, 2-1-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8668, Japan.
⁴ Axcelead Drug Discovery Partners, Inc., 2-26-1Muraoka-Higashi, Fujisawa-shi, Kanagawa, 251-0012, Japan.

Abstract

Cabozantinib is known as an inhibitor of receptor tyrosine kinases mainly targeting AXL receptor tyrosine kinase (AXL), MET proto-oncogene-encoded receptor tyrosine kinase (MET), and vascular endothelial growth factor receptor 2. Growth arrest-specific 6 (GAS6) and hepatocyte growth factor (HGF), the natural ligands of AXL and MET, respectively, are associated with the induction of cancer cell proliferation or metastasis. Currently, it is still unclear how cabozantinib regulates cancer cell migration and invasion by inhibiting AXL and MET. This study was conducted to investigate the mechanism underlying the anti-cancer effects of cabozantinib through regulation of AXL and MET signaling. The results of Boyden chamber assays showed that cancer cell migration was induced by GAS6 and HGF in SKOV3 cells in serum-free medium. Combinatorial treatment with GAS6 and HGF exerted an additive effect on cell migration. Furthermore, we examined the role of AXL and MET signaling in cell migration. Short interfering RNA targeting AXL and MET inhibited GAS6- and HGF-induced migration, respectively. Double knockdown of AXL and MET completely suppressed cell migration induced by combination treatment with GAS6 and HGF compared to AXL or MET inhibition alone. Finally, we investigated the effects of cabozantinib on cell migration and invasion. Cabozantinib inhibited AXL and MET phosphorylation and downregulated the downstream mediators, phosphorylated SRC in the presence of both GAS6 and HGF in SKOV3 cells. The cell migration and invasion induced by combined GAS6 and HGF treatment were suppressed by cabozantinib, but not by capmatinib, a selective MET inhibitor. Our data indicate that the GAS6-AXL and HGF-MET signal pathways markedly contribute to cancer cell migration and invasion in an independent manner, suggesting that simultaneous inhibition of these two pathways contributes to the anti-cancer effects of cabozantinib.

Keywords: AXL receptor tyrosine kinase; Cabozantinib; Cancer cell migration; Growth arrest-specific 6; Hepatocyte growth factor; MET proto-oncogene-encoded receptor tyrosine kinase.