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

J. J. Arcaroli, K. S. Quackenbush, A. Purkey, R. W. Powell, T. M. Pitts, S. Bagby, Aik-Choon Tan, B. Cross, K. McPhillips, E. K. Song, W. M. Tai, R. A. Winn, K. Bikkavilli, M. Vanscoyk, S. G. Eckhardt, W. A. Messersmith

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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 β-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.

Original languageEnglish
Pages (from-to)667-675
Number of pages9
JournalBritish Journal of Cancer
Volume109
Issue number3
DOIs
Publication statusPublished - 2013 Aug 6
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Arcaroli, J. J., Quackenbush, K. S., Purkey, A., Powell, R. W., Pitts, T. M., Bagby, S., Tan, A-C., Cross, B., McPhillips, K., Song, E. K., Tai, W. M., Winn, R. A., Bikkavilli, K., Vanscoyk, M., Eckhardt, S. G., & Messersmith, W. A. (2013). 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. British Journal of Cancer, 109(3), 667-675. https://doi.org/10.1038/bjc.2013.361