This study suggested that regorafenib suppressed tumor invasion, angiogenesis, anti-apoptosis and proliferation were associated with downregulating of EGFR/PKCδ/AKT/ERK/NF-κB pathway. In addition, death receptor dependent (extrinsic apoptosis) and mitochondria dependent (intrinsic apoptosis) apoptosis pathways were both activated by regorafenib treatment.

Active epidermal growth factor receptors (EGFR) signaling mediates the progression of colorectal cancer (CRC) through activation of downstream kinases and transcription factors. The increased expression of EGFR was associated with worse prognosis in patients with metastatic CRC (mCRC). Regorafenib, the oral kinase inhibitor approved for the treatment of mCRC, has been shown to reduce activation of downstream kinases of EGFR signal pathway in hepatocellular carcinoma and osteosarcoma. However, whether EGFR inactivation was participates in regorafenib-inhibited progression of CRC still remaining ambiguous. The major purpose of present study was to verify effect of regorafenib on EGFR signaling-mediated progression of CRC. Here, we investigated the effect of regorafenib or erlotinib (EGFR inhibitor) on tumor cell growth, invasion ability, apoptotic, and EGFR signal transduction in CRC in vitro and in vivo. Our results indicated regorafenib reduced EGF-induced EGFR and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity. Both regorafenib and erlotinib significantly reduced cell invasion ability, activation of protein kinase C-δ (PKCδ), protein kinase B (AKT), extracellular signal-regulated kinases (ERK), and NF-κB. Regorafenib can trigger the inhibition of tumor cell growth and the induction of apoptosis through extrinsic/intrinsic apoptosis pathways. In addition, the expression of NF-κB-mediated proteins involved in tumor progression was also suppressed by regorafenib treatment. Taken together, regorafenib acts as a inhibitor of EGFR signaling that attenuated the activation of EGFR and EGFR related downstream signaling cascades in CRC. Our results suggested that the suppression of EGFR signaling was associated with regorafenib-inhibited progression of CRC.