Receptor tyrosine kinase MET as potential target of multi-kinase inhibitor and radiosensitizer sorafenib in HNSCC.
Carcinoma, Squamous Cell
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Crizotinib
/ pharmacology
ErbB Receptors
/ antagonists & inhibitors
Head and Neck Neoplasms
/ drug therapy
Humans
Indoles
/ pharmacology
Phosphorylation
/ drug effects
Piperazines
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-met
/ antagonists & inhibitors
Sorafenib
/ pharmacology
Sulfonamides
/ pharmacology
MET
head and neck cancer
radiosensitization
sorafenib
targeted therapy
Journal
Head & neck
ISSN: 1097-0347
Titre abrégé: Head Neck
Pays: United States
ID NLM: 8902541
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
07
02
2018
revised:
13
06
2018
accepted:
18
07
2018
pubmed:
16
12
2018
medline:
28
5
2020
entrez:
16
12
2018
Statut:
ppublish
Résumé
The multi-kinase inhibitor sorafenib displays antitumoral effects in head and neck squamous cell carcinoma (HNSCC); however, the targeted kinases are unknown. Here we aimed to identify those kinases to determine the mechanism of sorafenib-mediated effects and establish candidate biomarkers for patient stratification. The effects of sorafenib and MET inhibitors crizotinib and SU11274 were analyzed using a slide-based antibody array, Western blotting, proliferation, and survival assays. X-rays were used for irradiations. Sorafenib inhibited auto-phosphorylation of epidermal growth factor receptor and MET, which has not been described previously. MET expression in HNSCC cells was not always associated with activity/phosphorylation. Furthermore, sorafenib-dependent cell kill and radiosensitization was not associated with MET level. Although MET inhibitors blocked proliferation, they caused only mild cytotoxicity and no radiosensitization. We identified MET as a new potential target of sorafenib. However, MET inhibition is not the cause for sorafenib-mediated cytotoxicity or radiosensitization.
Sections du résumé
BACKGROUND
The multi-kinase inhibitor sorafenib displays antitumoral effects in head and neck squamous cell carcinoma (HNSCC); however, the targeted kinases are unknown. Here we aimed to identify those kinases to determine the mechanism of sorafenib-mediated effects and establish candidate biomarkers for patient stratification.
METHODS
The effects of sorafenib and MET inhibitors crizotinib and SU11274 were analyzed using a slide-based antibody array, Western blotting, proliferation, and survival assays. X-rays were used for irradiations.
RESULTS
Sorafenib inhibited auto-phosphorylation of epidermal growth factor receptor and MET, which has not been described previously. MET expression in HNSCC cells was not always associated with activity/phosphorylation. Furthermore, sorafenib-dependent cell kill and radiosensitization was not associated with MET level. Although MET inhibitors blocked proliferation, they caused only mild cytotoxicity and no radiosensitization.
CONCLUSION
We identified MET as a new potential target of sorafenib. However, MET inhibition is not the cause for sorafenib-mediated cytotoxicity or radiosensitization.
Substances chimiques
((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
0
Indoles
0
Piperazines
0
Protein Kinase Inhibitors
0
Sulfonamides
0
Crizotinib
53AH36668S
Sorafenib
9ZOQ3TZI87
ErbB Receptors
EC 2.7.10.1
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
208-215Subventions
Organisme : Bundesministerium für Bildung und Forschung
ID : 02NUK032
Pays : International
Organisme : Hamburger Stiftung zur Förderung der Krebsbekämpfung
Pays : International
Organisme : Hamburger Krebsgesellschaft
Pays : International
Organisme : Bayer HealthCare
Pays : International
Informations de copyright
© 2018 Wiley Periodicals, Inc.