Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma.
Cancer Discov
; 4(10): 1154-67, 2014 Oct.
Article
em En
| MEDLINE
| ID: mdl-25104330
ABSTRACT
UNLABELLED Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD-low tumors without NOTCH1 mutations were resistant. SIGNIFICANCE:
NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
/
Carcinoma Adenoide Cístico
/
Secretases da Proteína Precursora do Amiloide
/
Neoplasias de Mama Triplo Negativas
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Cancer Discov
Ano de publicação:
2014
Tipo de documento:
Article