Abstract 1918: Anti-metastasis effect of EW-7197, a novel ALK5 inhibitor in both breast cancer cells in vitro and mouse model in vivo

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.1918-1918
• Main Authors: Kim, Seung W., Kim, Sol J., Park, Sang A., Kim, Min J., Kim, Dae-Kee, Sheen, Yhun Y.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-1918

We have synthesized new ALK5 inhibitor, EW-7197 and investigated their effects of on breast cancer cells as well as tumor bearing MMTV/cNeu transgenic mouse, 4T1 or 4T1-Luc cell-orthotopic implanted mouse models. The level of ß-casein or the number of metastatic nodule in the lung of the breast tumor bearing MMTV/cNeu transgenic mice or 4T1 cell-orthotopic implanted mice, respectively, were decreased by EW-7197 treatment. The treatment of the EW-7197 also inhibited the luciferase activity in the lung of 4T1-Luc cell-orthotopic implanted mouse compared to that of untreated animal. The levels of MMP2 and MMP9 were decreased in the lung and breast tumor of the EW-7197 treated mice. To determine the inhibitory effect of EW-7197 on TGF-β1-induced transcriptional activation, we performed luciferase reporter gene assay in breast cancer cells. EW-7197 effectively blocked TGF-β1-induced luciferase activity in the cells in a dose-dependent manner. TGFß signaling, the phosphorylation of smad2/3 was decreased by EW-7197. TGFß-stimulated mesenchymal markers of epithelial mesenchymal transition (EMT) were inhibited by ALK5 inhibitor concomitant treatment. Furthermore, EW-7197 rescued TGF-β-induced loss of E-cadherin in NMuMG cells. And also, EW-7197 showed higher inhibition on cell motility and cell invasion based on wound healing assay or invasion assay than SB-505124 and LY-2157299. In summary, EW-7197 have anti-metastatic effect on breast cancer cells in vitro as well as breast cancer models in vivo. This data strongly argue that the ALK5 inhibitor have anti-metastasis effects via inhibiting ALK5 activity in vivo and in vitro. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1918. doi:1538-7445.AM2012-1918