The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Abstract

VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signaltargeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI 50 > 10 mmol/L) in VEGFR signal-or MET signalindependent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685-96. Ó2013 AACR.

miR-26a/b Inhibit Tumor Growth and Angiogenesis by Targeting the HGF-VEGF Axis in Gastric Carcinoma

“…2E). Previous studies have found that HGF plays a significant role in tumor angiogenesis and induces VEGF expression in tumor cells [12][13][14][15]. A sketch map about HGF and its relationship with VEGF pathway is summarized in Fig.…”

MET/HGF targeted drugs as potential therapeutic strategies in non-small cell lung cancer

“…A combination of golvetanib and lenvatinib (VEGF and RET inhibitor) was able to overcome HGF-induced resistance in human primary cell cultures and cell lines, but further studies are needed to validate these results [185]. TAS-115 and T-1840383 are dual MET/VEGFR inhibitors that have shown in vitro and in vivo antiproliferative activity by blocking angiogenesis, with no toxic effects [186,187].…”

The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer

“…TAS-115 suppresses FMS-dependent signal in pre-osteoclasts and osteoclasts by inhibiting the phosphorylation of FMS. Several targets for TAS-115 were identified in a ProfilerPro kinase screen (4). However, it is well known that null mutation of FMS induces osteopetrosis because of the lack of osteoclast in op/op mice (20).…”

“…PC3 cells were cultured in RPMI 1640 medium with 10% FBS at 37°C under 5% CO 2 in air. TAS-115, a VEGFR/ MET-targeted kinase inhibitor, was prepared by Taiho Pharmaceutical Co., Ltd. (Tokyo Japan) as reported previously (4).…”

“…Inhibition of both VEGFR and MET signaling pathways has been reported to suppress tumor growth and angiogenesis synergistically (3), suggesting the possibility that the dual inhibition of VEGFR and MET signals may have potential effects on the prevention of tumor growth. Recently, Fujita et al (4) developed a novel VEGFR/MET-targeted tyrosine kinase inhibitor, TAS-115, and showed its antitumor properties in MET-amplified human cancer-bearing mice. In this study, we have investigated the effect of TAS-115 on prostate cancer cell metastasis to bone and a process associated with osteoclast activation.…”