American Association for Cancer Research
15357163mct130459-sup-mct-13-0459_fig_1_to_5_tab_1_to_3.pdf (243.35 kB)

Supplementary Figures 1 through 5 and Supplementary Tables 1 through 3 from The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has Marked In Vivo Antitumor Properties and a Favorable Tolerability Profile

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journal contribution
posted on 2023-04-03, 13:41 authored by Hidenori Fujita, Kazutaka Miyadera, Masanori Kato, Yayoi Fujioka, Hiroaki Ochiiwa, Jinhong Huang, Kimihiro Ito, Yoshimi Aoyagi, Toru Takenaka, Takamasa Suzuki, Satoko Ito, Akihiro Hashimoto, Takashi Suefuji, Kosuke Egami, Hideki Kazuno, Yoshimitsu Suda, Kazuto Nishio, Kazuhiko Yonekura

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.



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.