Regorafenib (BAY 73‐4506): Antitumor and antimetastatic activities in preclinical models of colorectal cancer

Abstract

Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient-derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC-related oncogenes. Regorafenib demonstrated significant inhibition of growth-factor-mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients.What's new?Regorafenib is a multikinase inhibitor with antiangiogenic activity recently approved in the US and in Europe for the treatment of metastatic colorectal cancer in patients who failed previous therapies. Here, a research team led by Bayer Pharma AG, the discoverer of the drug, confirms inhibition of key mediators of angiogenesis and lymphangiogenesis (VEGFR2 and VEGFR3) as the potential antiangiogenic mechanism of action of the drug. Regorafenib further inhibited growth of established and prevented formation of new liver metastases, and in combination with the chemotherapeutic drug irinotecan led to significant tumor growth delay in four patient-derived colorectal cancer xenograft models. The authors speculate that combination treatments including regorafenib may provide novel therapeutic opportunities for patients with therapy-resistant colorectal cancer.

The preclinical development of regorafenib for the treatment of colorectal cancer

“…Sorafenib was more potent in VEGFR3 and wild-type BRAF, and regorafenib seemed more potent in RAF1, BRAF(V600E), FGFR1, PDGFRB and C-Kit. In a report by Schmieder et al in 2013 [35], they specifically characterized the efficacy of regorafenib in CRC cells in vitro and in vivo, showing its efficacy on murine CRC liver metastasis models especially under combination with irinotecan. Abou-Elkacem et al analyzed the inhibitory effects of regorafenib on tumor growth, angiogenesis and metastasis using orthotopic xenograft CRC models [36].…”

“…In regards to regorafenib, as of March 2014 several articles with CRC cells have been reported [6,[35][36][37] but those with other types of malignant cells are still limited. In studies by Wilhelm et al in 2011 [6], several types of cancer cells including CRC, HCC, melanoma and gastrointestinal stromal tumor (GIST) as well as HUVECs, human aortic smooth muscle cells and NIH-3T3 cells were analyzed for regorafenib, where studies revealed that regorafenib inhibited angiogenic kinases such as VEGFR1, VEGFR2, VEGFR3, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2, PDGFRB and fibroblast growth factor receptor 1 (FGFR1), as well as mutant oncogenic kinases of C-Kit, ret proto-oncogene (RET) and BRAF.…”

Response to regorafenib at an initial dose of 120 mg as salvage therapy for metastatic colorectal cancer

“…Therefore, treatments after first-line chemotherapy are important and further therapeutic agents are required. Regorafenib (Reg) is an oral multikinase inhibitor targeting multiple tumor pathways, such as proliferation (KIT, BRAF, RAF-1 and RET), tumor microenvironment signaling (platelet-derived growth factor receptor-β and fibroblast growth factor receptor) and neoangiogenesis [vascular endothelial growth factor receptor (VEGFR)1-3 and angiopoietin-1 receptor] (13). An international phase III study (CORRECT) was conducted: A total of 760 patients with mCRC, who were refractory or intolerant to standard chemotherapy including 5-FU, L-OHP, CPT-11 and molecular-targeted drugs, such as anti-VEGF antibody and anti-epidermal growth factor receptor (EGFR) antibody, were randomized in a 2:1 ratio to receive Reg or placebo.…”

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab

“…Regorafenib is an oral multikinase inhibitor, that could target three key oncogenic pathways, such as (i) cell growth by inhibition of KIT, RET, RAF-1, and BRAF; (ii) tumor-induced angiogenes is by targeting VEGFR1, 2, and 3, and the tyrosine kinase with immunoglobulin and EGF homology domain 2 (TIE2); and (iii) tumor microenvironment by blocking platelet-derived growth factor receptor-b (PDGR-b) and FGFR (17)(18)(19). In preclinical studies, regorafenib exhibited antitumor activity in different tumor xenografts (17).…”