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.
Highlights
Cabozantinib is a small-molecule tyrosine kinase inhibitor (TKI) that uniquely inhibits the phosphorylation of AXL, MET proto-oncogene-encoded receptor tyrosine kinase (MET), and vascular endothelial growth factor receptor 2 (VEGFR2) along with RET and ROS1 [1,2]
Double knockdown of AXL and MET completely suppressed cell migration induced by combination treatment with Growth arrest-specific 6 (GAS6) and hepatocyte growth factor (HGF) compared to AXL or MET inhibition alone
Combined treatment with short interfering RNA (siRNA) targeting AXL and MET downregulated AXL, phosphorylated AXL (pAXL), MET, and phosphorylated MET (pMET) (Fig. 2B). siRNA-treated cells were seeded into the upper chamber, and GAS6, HGF, or a combination of GAS6 and HGF was added to the lower chamber
Summary
Cabozantinib is a small-molecule tyrosine kinase inhibitor (TKI) that uniquely inhibits the phosphorylation of AXL, MET, and vascular endothelial growth factor receptor 2 (VEGFR2) along with RET and ROS1 [1,2]. This compound, as a single agent, has been approved in several countries or regions including the US and the EU for treating progressive metastatic medullary thyroid carcinoma, advanced renal cell carcinoma (RCC), and recently, hepatocellular carcinoma. Genetic alternations and overexpression of MET are broadly observed in various cancer types such as lung cancer, breast cancer and glioblastoma, and abnormal activation of HGF-MET signaling is involved in tumor progression and metastasis [4,5]. It has been reported that AXL and MET are involved in acquired resistance to sunitinib and that cabozantinib has anti-tumor activity against sunitinib-resistant cells both in vitro and in vivo [17]
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