Molecular insight of regorafenib treatment for colorectal cancer.
Angiogenesis Inhibitors
/ pharmacology
Antineoplastic Agents
/ pharmacology
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Biomarkers, Tumor
Colorectal Neoplasms
/ drug therapy
Humans
Macrophages
/ drug effects
Mutation
Phenylurea Compounds
/ administration & dosage
Proto-Oncogene Proteins B-raf
/ genetics
Pyridines
/ administration & dosage
Receptor, TIE-2
/ antagonists & inhibitors
Receptors, Vascular Endothelial Growth Factor
/ antagonists & inhibitors
ras Proteins
/ genetics
Anti-angiogenesis
Biomarker
Colorectal cancer
Immunotherapy
Regorafenib
Tumor microenvironment
Journal
Cancer treatment reviews
ISSN: 1532-1967
Titre abrégé: Cancer Treat Rev
Pays: Netherlands
ID NLM: 7502030
Informations de publication
Date de publication:
Dec 2019
Dec 2019
Historique:
received:
06
09
2019
revised:
22
10
2019
accepted:
23
10
2019
pubmed:
13
11
2019
medline:
18
12
2019
entrez:
13
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31715423
pii: S0305-7372(19)30130-6
doi: 10.1016/j.ctrv.2019.101912
pmc: PMC7491975
mid: NIHMS1623147
pii:
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Antineoplastic Agents
0
Biomarkers, Tumor
0
Phenylurea Compounds
0
Pyridines
0
regorafenib
24T2A1DOYB
Receptor, TIE-2
EC 2.7.10.1
Receptors, Vascular Endothelial Growth Factor
EC 2.7.10.1
TEK protein, human
EC 2.7.10.1
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
101912Subventions
Organisme : NCI NIH HHS
ID : P30 CA014089
Pays : United States
Informations de copyright
Published by Elsevier Ltd.
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