Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors.
J Exp Clin Cancer Res
; 29: 96, 2010 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-20633291
ABSTRACT
BACKGROUND:
Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).METHODS:
This study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays.RESULTS:
Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC50 = 18 nM) and exon 11 (V560 D, IC50 = 5 nM; Delta552-559, IC50 = 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC50 = 77 nM; V560D/T670I, IC50 = 277 nM; Y823 D, IC50 = 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC50 > 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC50 values in good agreement with those observed in the autophosphorylation assays.CONCLUSIONS:
In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Niacinamida
/
Proteínas Proto-Oncogênicas c-kit
/
Tumores do Estroma Gastrointestinal
/
Indóis
/
Mutação
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Exp Clin Cancer Res
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos