Colorectal cancer (CRC) is the third most common
cancer, and is one of the leading causes of
cancer-related death worldwide. At the time of diagnosis, about 20% of patients with CRC present metastatic disease.
Regorafenib, an oral multi-
kinase inhibitor, has been demonstrated the efficacy and tolerability in patients with metastatic CRC.
Oxaliplatin is a frontline treatment regimen for CRC, and combination treatments with
oxaliplatin and other chemotherapeutic agents exert superior
therapeutic effects. However, side effects and drug resistance limited their further clinical application. Here, we found that combined treatment with
regorafenib and
oxaliplatin synergistically enhanced anti-
tumor activities in CRC by activating
reactive oxygen species (ROS) mediated endoplasmic reticulum (ER) stress,
C-Jun-amino-terminal kinase (JNK) and p38 signaling pathways.
Regorafenib promoted ROS production by suppressing the expression of
selenoprotein S (SELENOS). Knocking down SELENOS sensitized ROS-mediated anti-
tumor effects of
regorafenib in CRC cells. Furthermore, mouse xenograft models demonstrated that synergistic anti-
tumor effects of combined treatment with
regorafenib and
oxaliplatin. This study provided solid experimental evidences for the combined treatment with
regorafenib and
oxaliplatin in CRC.