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

Research output: Contribution to journalArticle

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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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Amyloid Precursor Protein Secretases
Wnt Signaling Pathway
Colorectal Neoplasms
Gene Knockdown Techniques
Neoplasms
HCT116 Cells
Catenins
Immunoblotting
Heterografts
Genes
2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

In: British Journal of Cancer, Vol. 109, No. 3, 06.08.2013, p. 667-675.

Research output: Contribution to journalArticle

Arcaroli, JJ, Quackenbush, KS, Purkey, A, Powell, RW, Pitts, TM, Bagby, S, Tan, A-C, Cross, B, McPhillips, K, Song, EK, Tai, WM, Winn, RA, Bikkavilli, K, Vanscoyk, M, Eckhardt, SG & Messersmith, WA 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, vol. 109, no. 3, pp. 667-675. https://doi.org/10.1038/bjc.2013.361
Arcaroli, J. J. ; Quackenbush, K. S. ; Purkey, A. ; Powell, R. W. ; Pitts, T. M. ; Bagby, S. ; Tan, Aik-Choon ; Cross, B. ; McPhillips, K. ; Song, E. K. ; Tai, W. M. ; Winn, R. A. ; Bikkavilli, K. ; Vanscoyk, M. ; Eckhardt, S. G. ; Messersmith, W. A. / 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. In: British Journal of Cancer. 2013 ; Vol. 109, No. 3. pp. 667-675.
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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.",
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AU - Purkey, A.

AU - Powell, R. W.

AU - Pitts, T. M.

AU - Bagby, S.

AU - Tan, Aik-Choon

AU - Cross, B.

AU - McPhillips, K.

AU - Song, E. K.

AU - Tai, W. M.

AU - Winn, R. A.

AU - Bikkavilli, K.

AU - Vanscoyk, M.

AU - Eckhardt, S. G.

AU - Messersmith, W. A.

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N2 - 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.

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