Abstract
VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signal-targeted 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 (GI50 > 10 μmol/L) in VEGFR signal- or MET signal-independent 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.
Highlights
VEGF is a key factor involved in tumor vascularization [1]
Monotherapy with any of these drugs is effective against some carcinomas [e.g., gastrointestinal stromal tumor (GIST), renal cell carcinoma, hepatocellular carcinoma, and pancreatic neuroendocrine tumors), suggesting that the inhibition of the VEGF/VEGF receptor (VEGFR) pathway is a valid strategy for the treatment of cancer
TAS-115 markedly inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2), AKT, focal adhesion kinase (FAK), S6, and STAT3 at a concentration of more than 0.03 mmol/L (Fig. 1D). These results indicate that TAS-115 suppresses signal transduction in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/ AKT pathways by inhibiting MET in MET-amplified cancer cells
Summary
VEGF is a key factor involved in tumor vascularization [1]. An association between the VEGF expression level and patient prognosis has been shown for many carcinomas [2,3,4,5,6,7]. Bevacizumab, sunitinib, sorafenib, pazopanib, and axitinib are drugs that exert antitumor activities by inhibiting tumor vascularization through the suppression of VEGF function [8]. Monotherapy with any of these drugs is effective against some carcinomas [e.g., gastrointestinal stromal tumor (GIST), renal cell carcinoma, hepatocellular carcinoma, and pancreatic neuroendocrine tumors), suggesting that the inhibition of the VEGF/VEGFR pathway is a valid strategy for the treatment of cancer. Authors' Affiliations: 1Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki; and 2Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
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