胰管腺癌（PDAC）表现出显著的细胞外基质（ECM）丰富反应，这是由于过量的转化生长因子β（TGF-β）产生的，导致肿瘤进展和转移。此外，TGF-β信号通路有助于快速获得耐药性和不完全应答吉西他滨。最近，在PDAC治疗中选择性TGF-β信号通路抑制剂表现出了希望，特别是作为增强化疗反应的选择。在这里，我们调查了小分子TGF-β受体I激酶抑制剂（vactosertib / EW-7197）在吉西他滨存在下的协同抗癌效应，以及其在胰腺癌中的作用机制。vactosertib通过协同抑制其生存能力，使胰腺癌细胞对吉西他滨产生敏感性。重要的是，在与吉西他滨结合使用时，vactosertib显著减弱了胰腺癌中主要的ECM成分表达，包括胶原蛋白、纤维连接蛋白和α-SMA，相比之下，吉西他滨单用。这导致线粒体介导的凋亡、吉西他滨介导的细胞毒性以及vactosertib抑制肿瘤ECM的强效诱导。此外，该联合治疗通过抑制迁移和侵袭减少了转移，并通过抑制胰腺癌细胞中的TGF-β / Smad2途径表现出协同的抗癌活性。此外，联合治疗在原位模型中显著抑制了肿瘤生长。因此，我们的发现表明vactosertib通过抑制TGF-β / Smad2信号通路从而抑制ECM成分生产，从而协同增强吉西他滨的抗肿瘤活性。这表明vactosertib和吉西他滨的联合可能是胰腺癌患者的潜在治疗选择。 版权所有©2023 The Authors。由Elsevier Masson SAS出版。保留所有权利。

Pancreatic ductal adenocarcinoma (PDAC) exhibits a pronounced extracellular matrix (ECM)-rich response, which is produced by an excessive amount of transforming growth factor β (TGF-β), resulting in tumor progression and metastasis. In addition, TGF-β signaling contributes to rapidly acquired resistance and incomplete response to gemcitabine. Recently, selective inhibitors of the TGF-β signaling pathway have shown promise in PDAC treatment, particularly as an option for augmenting responses to chemotherapy. Here, we investigated the synergistic anticancer effects of a small-molecule TGF-β receptor I kinase inhibitor (vactosertib/EW-7197) in the presence of gemcitabine, and its mechanism of action in pancreatic cancer. Vactosertib sensitized pancreatic cancer cells to gemcitabine by synergistically inhibiting their viability. Importantly, the combination of vactosertib and gemcitabine significantly attenuated the expression of major ECM components, including collagens, fibronectin, and α-SMA, in pancreatic cancer compared with gemcitabine alone. This resulted in potent induction of mitochondrial-mediated apoptosis, gemcitabine-mediated cytotoxicity, and inhibition of tumor ECM by vactosertib. Additionally, the combination decreased metastasis through inhibition of migration and invasion, and exhibited synergistic anti-cancer activity by inhibiting the TGF-β/Smad2 pathway in pancreatic cancer cells. Furthermore, co-treatment significantly suppressed tumor growth in orthotopic models. Therefore, our findings demonstrate that vactosertib synergistically increased the antitumor activity of gemcitabine via inhibition of ECM component production by inhibiting the TGF-β/Smad2 signaling pathway. This suggests that the combination of vactosertib and gemcitabine may be a potential treatment option for patients with pancreatic cancer.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.