A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3.
Clin Cancer Res
; 17(22): 7127-38, 2011 Nov 15.
Article
en En
| MEDLINE
| ID: mdl-21918175
ABSTRACT
PURPOSE:
The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase. EXPERIMENTALDESIGN:
Studies were conducted using a series of in vitro and in vivo biochemical and biological experiments.RESULTS:
INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers.CONCLUSIONS:
Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Benzamidas
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Transducción de Señal
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Compuestos Bicíclicos Heterocíclicos con Puentes
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Proteínas Proto-Oncogénicas c-met
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Receptor Cross-Talk
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Receptores ErbB
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Neoplasias Experimentales
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Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos