Abstract 2034: Traf2-and Nck-interacting kinase (TNIK) inhibitor, NCB-0846, suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer

Abstract

Abstract Epithelial mesenchymal transition (EMT) has been implicated in cancer cell migration, invasion, and metastasis. Transforming growth factor-β (TGF-β) signal was known to be an essential EMT promotor. Development of therapeutics for targeting EMT through the TGF-β signal may be beneficial for the management of cancer metastasis. Recently, we found that a Traf2- and Nck-interacting kinase (TNIK) inhibitor, named NCB-0846, was capable of attenuating tumor-initiating cells among human colorectal cancer (1, 2). The cross link between EMT and cancer stemness has been revealed in several studies. Therefore we evaluated whether this small-molecule compound could have efficacy to inhibit TGF-β-induced EMT. NCB-0846 reduced the expression of mesenchymal markers (Vimentin and N-cadherin) and upregulated the expression of epithelial marker E-cadherin in A549 and H2228 cells. NCB-0846 suppressed the phosphorylation and nuclear translocation of Smad proteins and also inhibited migration, invasion, and metastasis. NCB-0846 inhibited TGF-β1-induced EMT through the down-regulation of TGFBR1 in mRNA levels. MiR-186-5p and miR-320 family were identified as candidate miRNAs that could target TGFBR1 and inhibited TGFBR1 protein expression.NCB-0846 might be a novel therapeutics drugs that targets the invasion and metastasis through inhibiting TGF-β-induced EMT in lung cancer. 1. Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacology & therapeutics. 2015;156:1-9. Epub 2015/11/07.2. Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, et al. TNIK inhibition abrogates colorectal cancer stemness. Nature communications. 2016;7:12586. Epub 2016/08/27. Citation Format: Teppei Sugano, Mari Masuda, Yuko Uno, Naoko Goto, Masahiro Seike, Masaaki Sawa, Akihiko Gemma, Tesshi Yamada. Traf2-and Nck-interacting kinase (TNIK) inhibitor, NCB-0846, suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2034.