Vactosertib, TGF-β receptor I inhibitor, augments the sensitization of the anti-cancer activity of gemcitabine in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) exhibits a pronounced extracellular matrix (ECM)-rich response, which is produced by an excessive amount of transforming growth factor beta (TGF-beta), resulting in tumor progression and metastasis. In addition, TGF-beta signaling contributes to rapidly acquired resistance and incomplete response to gemcitabine. Recently, selective inhibitors of the TGF-beta 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-beta 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 alpha-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-beta/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-beta/Smad2 signaling pathway. This suggests that the combination of vactosertib and gemcitabine may be a potential treatment option for patients with pancreatic cancer.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive production of transforming growth factor beta (TGF-beta), resulting in tumor progression and resistance to gemcitabine. A small-molecule TGF-beta receptor I kinase inhibitor, vactosertib, demonstrated synergistic anticancer effects with gemcitabine by inhibiting viability, decreasing expression of ECM components, inducing apoptosis, and inhibiting migration and invasion in pancreatic cancer cells. The combination treatment also suppressed tumor growth and inhibited the TGF-beta/Smad2 signaling pathway. These findings suggest that vactosertib and gemcitabine may be a potential treatment option for pancreatic cancer patients.