title: 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.
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Roberta
authors.initials: R
authors.lastname: Schmieder
authors.forename: Jens
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Michael
authors.initials: M
authors.lastname: Becker
authors.forename: Ajay
authors.initials: A
authors.lastname: Bhargava
authors.forename: Tina
authors.initials: T
authors.lastname: Müller
authors.forename: Nicole
authors.initials: N
authors.lastname: Kahmann
authors.forename: Peter
authors.initials: P
authors.lastname: Ellinghaus
authors.forename: Robert
authors.initials: R
authors.lastname: Adams
authors.forename: André
authors.initials: A
authors.lastname: Rosenthal
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Thierauch
authors.forename: Arne
authors.initials: A
authors.lastname: Scholz
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wilhelm
authors.forename: Dieter
authors.initials: D
authors.lastname: Zopf
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; D000077150:Oxaliplatin; C559147:regorafenib; D000077146:Irinotecan; C581309:FLT4 protein, human; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D002166:Camptothecin
keywords: CRC; antimetastasis; antitumorigenesis; multikinase inhibitor; regorafenib