TGF-β inhibitor LY2157299 (galunisertib) in combination with standard chemotherapy and inhibition of signaling to pSmad and EMT and suppression of tumor growth in gastric cancer.

50 Background: TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) of tumor cells, thus producing tumor progression, invasion, and metastasis. Therefore, this signaling has been expected to be a new target of cancer therapy. In this study, we evaluated the antitumor effect of LY2157299, a TGF-βR1 kinase inhibitor, alone and in combination with 5-fluorouracil (5-FU) or paclitaxel (PTX), key agents in the treatment of gastric cancer (GC). Methods: TGF-β inhibition impedes phosphorylation of Smad2 and induces the expression of vimentin, an EMT marker. Vimentin expression was examined +/- LY2157299 by western blot. The phenotypic change of human GC cell, 44As3-Luc after TGF-β and LY2157299 treatment was assessed by Matrigel migration/invasion assay. The in vitro cytocidal effect and in vivo antitumor effect of LY2157299 alone or with either 5-FU or PTX were evaluated by water soluble tetrazolium-1 (WST-1) assay and by xenograft mouse model, respectively. Results: The phosphorylation of...