Cited by 191Colorectal Cancer Treatments and StudiesAngiogenesis and VEGF in CancerCancer Immunotherapy and Biomarkers

Molecular Insight of Regorafenib Treatment for Colorectal Cancer

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Arai, Hiroyuki, Battaglin, Francesca, Wang, Jingyuan, Lo, Jae Ho, Soni, Shivani, Zhang, Wu, Lenz, Heinz-Josef·2019·Cancer Treatment Reviews

Abstract

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.

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Authors
Arai, H., Battaglin, F., Wang, J., Lo, J. H., Soni, S., Zhang, W., & Lenz, H.-J.
Affiliations
University of Southern California (US)
Corresponding author
  • Battaglin, Francesca
  • Wang, Jingyuan
  • Lo, Jae Ho
  • Zhang, Wu
  • Lenz, Heinz-Josef
Venue
Cancer Treatment Reviews
Publisher
Elsevier BV
Published
2019-12
Volume
81
Pages
101912
ISSN
0305-7372 (ISSN-L)
OpenAlex
W2982376008
Cited by
191
References
96
Citations by year
2026: 15 · 2025: 22 · 2024: 51 · 2023: 30 · 2022: 28 · 2021: 32 · 2020: 13
FWCI
1.74
Type
journal article
Language
en
Open access
Locations
  • Cancer Treatment Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (P30CA014089)
  • Dhont Family Foundation
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
regorafenib, metastatic colorectal cancer, multikinase inhibitor, angiogenesis inhibition, VEGF receptor blockade, Tie2, tumor microenvironment, FGF signaling, PDGF signaling, tumor-associated macrophages, antitumor immunity, immune checkpoint inhibitors, predictive biomarkers, Raf-1
MeSH terms
Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Humans, Macrophages, Mutation, Phenylurea Compounds, Pyridines, Biomarkers, Tumor, Colorectal Neoplasms, ras Proteins, Angiogenesis Inhibitors, Receptors, Vascular Endothelial Growth Factor, Receptor, TIE-2, Proto-Oncogene Proteins B-raf

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