Molecular insight of regorafenib treatment for colorectal cancer

Cancer Treat Rev. 2019 Dec:81:101912. doi: 10.1016/j.ctrv.2019.101912. Epub 2019 Oct 28.


Regorafenib is a multi-targeting kinase inhibitor approved for the treatment of metastatic colorectal cancer patients in refractory to standard chemotherapy. Similarly to sorafenib, this agent was originally developed as a RAF1 inhibitor. However, the kinase inhibitory profile is distinct from sorafenib. A broad-spectrum of kinase inhibition induces wide-range drug sensitivity, irrespective of mutation status of major oncogenes. This agent's main therapeutic effects are anti-angiogenesis and the remodeling of tumor microenvironment through several mechanisms of action. The dual blockade of VEGF receptors and TIE2 can lead to both additive anti-angiogenesis effects and the suggestive unique regulation of vessel stability. Additionally, it inhibits molecular escape pathways to VEGF inhibition (e.g., FGF, PIGF, and PDGF signaling), enabling its continuous antiangiogenic effect even in tumors resistant to VEGF inhibitors. Furthermore, regorafenib has the important effect of enhancing anti-tumor immunity via macrophage modulation. Based on this concept, clinical trials have been recently launched for the development of a combination strategy with immune checkpoint inhibitors. Contrary to regorafenib induced clinical benefits and advances in the novel strategy, currently no predictive biomarkers have been identified. In the present review, we revisit and summarize regorafenib's unique mechanisms of action. The review could highlight molecular insights and provide some perspective for the search of predictive biomarkers used in metastatic colorectal cancer patients treated with regorafenib.

Keywords: Anti-angiogenesis; Biomarker; Colorectal cancer; Immunotherapy; Regorafenib; Tumor microenvironment.

Publication types

  • Review

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Humans
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mutation
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacology*
  • Phenylurea Compounds / therapeutic use
  • Proto-Oncogene Proteins B-raf / genetics
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Receptor, TIE-2 / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • ras Proteins / genetics


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Phenylurea Compounds
  • Pyridines
  • regorafenib
  • Receptor, TIE-2
  • Receptors, Vascular Endothelial Growth Factor
  • TEK protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • ras Proteins