Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.
Br J Cancer
; 109(3): 667-75, 2013 Aug 06.
Article
em En
| MEDLINE
| ID: mdl-23868008
ABSTRACT
BACKGROUND:
Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014.METHODS:
A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting.RESULTS:
We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active ß-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours.CONCLUSION:
This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tetra-Hidronaftalenos
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Valina
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Neoplasias Colorretais
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Receptores Notch
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Secretases da Proteína Precursora do Amiloide
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Via de Sinalização Wnt
Tipo de estudo:
Clinical_trials
Limite:
Adult
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Aged
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Animals
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Female
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Humans
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Middle aged
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article