PDF - 243KB, Supplementary Figure S1. Growth inhibition of TAS-115 against MET amplified cancer cell lines. Supplementary Figure S2. Kinase inhibitor-induced cell damage in rat cardiomyocytes after 96 h of treatment. Supplementary Figure S3. Gene expression changes in mice bearing human gastric cancer SC-9 after TAS-115 or sunitinib treatment. Supplementary Figure S4. Anti-tumor efficacy of TAS-115 against athymic mice transplanted with MET-amplified human gastric cancer Hs746T (A), NUGC-4 (B). Supplementary Figure S5. The inhibitory activity of sunitinib against adenosine monophosphate (AMP)-activated protein kinase (AMPK). Supplementary Table S1. Kinase inhibitory activity of TAS-115 and sunitinib against 192 kinases. Supplementary Table S2. Cell growth inhibition of TAS-115, sunitinib, sorafenib and crizotinib against MET-amplified or MET-inactivated cancer cell lines. Supplementary Table S3. Median survival times (MST) in the NUGC-4 peritoneal dissemination model after TAS-115 or sunitinib treatment.
ARTICLE 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. Mol Cancer Ther; 12(12); 2685–96. ©2013 AACR.
