Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a ?-secretase inhibitor, in a preclinical colorectal explant model.

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 ?-secretase inhibitor (GSI) PF-03084014. METHODS:A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPj? 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 ?-catenin. In addition, knockdown of the RBPj? 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 ?-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.

SUBMITTER: Arcaroli JJ 

PROVIDER: S-EPMC3738122 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature