Abstract
Foretinib, a multiple kinase inhibitor undergoing clinical trials, could suppress the activity of hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, Foretinib may inhibit two critical lymphangiogenic signaling receptors VEGFR-3 and TIE-2. However, the effect of Foretinib on lymphatic endothelial cells (LECs) in vitro and lymphangiogenesis in vivo is still unknown. We found Foretinib decreased basal- and HGF-induced c-MET activity at low concentrations. However, Foretinib only reduced the proliferation of pancreatic cancer cells at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells. Foretinib inhibited VEGF-A, VEGF-C and Angiopoetin-2 (ANG-2)-stimulated tube formation and sprouting of LECs by reducing VEGFR-2, VEGFR-3 and TIE-2 activation and increased apoptosis of LECs. In xenograft animal study, Foretinib suppressed tumor growth by inhibiting proliferation, angiogenesis and lymphangiogenesis. Additionally, Foretinib inhibited angiogenesis and lymphangiogenesis more significantly and exhibited low detrimental effect in orthotopic animal study. Collectively, we suggested that Foretinib simultaneously inhibits cancer cells and LECs to reduce pancreatic tumor growth in vivo and demonstrated for the first time that Foretinib suppresses angiogenesis and lymphangiogenesis by blocking VEGFR-2/3 and TIE-2 signaling.
Highlights
Foretinib was developed as an ATP-binding site competitor to inhibit receptor tyrosine kinases (RTKs) [1]
Hepatocyte growth factor (HGF) increased phosphorylation of c-MET and its downstream AKT and ERK which could be significantly inhibited by Foretinib (Fig. 1D)
Foretinib only showed significant anti-cancer activity at high concentration reflecting the intrinsic chemoresistance of pancreatic cancer cells and additional RTKs beside c-MET are important for the proliferation and survival of these cancer cells
Summary
Foretinib was developed as an ATP-binding site competitor to inhibit receptor tyrosine kinases (RTKs) [1]. Because Foretinib is a potent inhibitor of c-MET, this drug suppressed different c-MET-activated cell lines and reduced tumor growth in different animal studies [2,3,4]. Accumulating evidence indicated that Foretinib targeted additional kinases to reduce tumor growth. Foretinib suppressed c-JUN N-terminal kinase (JNK) to induce mitotic catastrophe in chronic myelogenous leukemia cells [5] and inhibited the TAM family of RTKs including AXL, TYRO3 and MER to kill glioblastoma cells [6]. Foretinib was shown to be a potent inhibitor of ROS1 fusion oncogenes which occurred in lung adenocarcinoma, cholangiocarcinoma and glioblastoma [7]
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