Dasabuvir Suppresses Esophageal Squamous Cell Carcinoma Growth As a Novel ROCK1 Inhibitor
Abstract Background: Esophageal squamous cell carcinoma (ESCC) is a high recurrence rate of upper-digestive cancer with a low 5-year survival rate. Therefore, there is an urgent need for effective chemopreventive drugs that can extend the survival rate of patients. Through screening of FDA-approved drugs, dasabuvir was found to suppress ESCC proliferation. Methods: Cell number count assay was used to screen for drugs with inhibitory effect on ESCC cells and detect the inhibitory effect of dasabuvir on proliferation of ESCC cells KYSE150 and KYE450. Phosphoproteomics and proteomics were used to investigate the mechanism of dasabuvir inhibiting ESCC. In vitro kinase assay was used to verify the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation by ROCK1 by dasabuvir. The PDX model was used to test the inhibitory effect of dasabuvir on ESCC in vivo.Results: In this study, we found that dasabuvir is a novel inhibitor of Rho-associated protein kinase 1 (ROCK1). Dasabuvir inhibited the growth of the KYSE150 and KYSE450 ESCC cell lines in a time and dose-dependent manner and arrested cell cycle at the G0/G1 phase. The antitumor activity was validated in vivo using a patient-derived xenograft tumor model in mice. Dasabuvir inhibited the activation of ERK1/2 by ROCK1 and downregulated cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Conclusions: These results provide the first evidence that dasabuvir serves as a ROCK1 inhibitor, suppresses ESCC growth in vivo and in vitro, and arrests the cell cycle through the ROCK1/ERK signaling pathway.