Lung squamous cell carcinoma (LSCC) is a common type of non-small-cell lung cancer (NSCLC) and lacks effective treatment. Regorafenib, an oral multikinase inhibitor, has demonstrated promising anti-tumor activity in various solid tumors. To study whether regorafenib inhibits LSCC cells, we investigate the compound in several LSCC cell lines and explore the possible mechanism. In this study, we confirmed that regorafenib had anti-proliferation effect on LSCC cell lines by inducing G0/G1 arrest. In addition, glycogen synthase kinase 3 beta (GSK3 beta remained at the same level and Ser9 phosphorylation of GSK3 beta decreased with increasing incubation time and increasing regorafenib concentration in LSCC cells. GSK3 beta inhibition enhanced the anti-tumor activity of regorafenib. Thus, GSK3 beta activation restricted the anticancer effect of regorafenib on LSCC. In conclusion, regorafenib might be a promising drug for LSCC therapy. GSK3 beta might be a potential target to increase the anti-tumor effect of regorafenib in LSCC cells. (C) 2018 Elsevier Inc. All rights reserved.