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; A. C. Tan; B. Cross; K. McPhillips; E. K. Song; W. M. Tai; R. A. Winn; K. Bikkavilli; M. Vanscoyk; S. G. Eckhardt; W. A. Messersmith

doi:10.1038/bjc.2013.361

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, A. C. Tan, B. Cross, K. McPhillips, E. K. Song, W. M. Tai, R. A. Winn, K. Bikkavilli, M. Vanscoyk, S. G. Eckhardt, W. A. Messersmith

Department of Computer Science and Engineering

Research output: Contribution to journal › Article › peer-review

34 Citations (Scopus)

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 language	English
Pages (from-to)	667-675
Number of pages	9
Journal	British Journal of Cancer
Volume	109
Issue number	3
DOIs	https://doi.org/10.1038/bjc.2013.361
Publication status	Published - 2013 Aug 6

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/bjc.2013.361

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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

Arcaroli, JJ, Quackenbush, KS, Purkey, A, Powell, RW, Pitts, TM, Bagby, S, Tan, AC, 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

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title = "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",

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.",

author = "Arcaroli, {J. J.} and Quackenbush, {K. S.} and A. Purkey and Powell, {R. W.} and Pitts, {T. M.} and S. Bagby and Tan, {A. C.} and B. Cross and K. McPhillips and Song, {E. K.} and Tai, {W. M.} and Winn, {R. A.} and K. Bikkavilli and M. Vanscoyk and Eckhardt, {S. G.} and Messersmith, {W. A.}",

note = "Funding Information: This work was supported by a Pfizer IIR grant.",

year = "2013",

month = aug,

day = "6",

doi = "10.1038/bjc.2013.361",

language = "English",

volume = "109",

pages = "667--675",

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T1 - 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

AU - Arcaroli, J. J.

AU - Quackenbush, K. S.

AU - Purkey, A.

AU - Powell, R. W.

AU - Pitts, T. M.

AU - Bagby, S.

AU - Tan, A. C.

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.

N1 - Funding Information: This work was supported by a Pfizer IIR grant.

PY - 2013/8/6

Y1 - 2013/8/6

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.

AB - 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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ER -

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

Abstract

ASJC Scopus subject areas

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