HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer

Pancreatic Cancer is one of the most aggressive solid malignancies prone to metastasis. Epithelial-mesenchymal transition (EMT) contributes to Cancer invasiveness and drug resistance. In this study, we investigated whether HS-173, a novel PI3K Inhibitor blocked the process of EMT in pancreatic Cancer. HS-173 inhibited the growth of pancreatic Cancer cells in a dose- and time-dependent manner. Moreover, it significantly suppressed the TGF-β-induced migration and invasion, as well as reversed TGF-β-induced mesenchymal cell morphology. Also, HS-173 reduced EMT by increasing epithelial markers and decreasing the mesenchymal markers by blocking the PI3K/Akt/mTOR and SMAD2/3 signaling pathways in pancreatic Cancer cells. In addition, HS-173 clearly suppressed tumor growth without drug toxicity in both xenograft and orthotopic mouse models. Furthermore, to explore the anti-metastatic effect of HS-173, we established pancreatic Cancer metastatic mouse models and found that it significantly inhibited metastatic dissemination of the primary tumor to liver and lung. Taken together, our findings demonstrate that HS-173 can efficiently suppress EMT and metastasis by inhibiting PI3K/Akt/mTOR and SMAD2/3 signaling pathways, suggesting it can be a potential candidate for the treatment of advanced stage pancreatic Cancer.