Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma.
Science
; 326(5952): 572-4, 2009 Oct 23.
Article
en En
| MEDLINE
| ID: mdl-19726788
ABSTRACT
The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piridinas
/
Neoplasias Encefálicas
/
Receptores Acoplados a Proteínas G
/
Proteínas Hedgehog
/
Anilidas
/
Meduloblastoma
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Science
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos