Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma.
Cancer Cell
; 27(3): 327-41, 2015 Mar 09.
Article
em En
| MEDLINE
| ID: mdl-25759019
ABSTRACT
Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Neoplasias Cutâneas
/
Carcinoma Basocelular
/
Resistencia a Medicamentos Antineoplásicos
/
Receptores Acoplados a Proteínas G
/
Anilidas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cancer Cell
Ano de publicação:
2015
Tipo de documento:
Article