Oncotarget

Research Papers:

The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance

Kevin S. Quackenbush, Stacey Bagby, Wai Meng Tai, Wells A. Messersmith, Anna Schreiber, Justin Greene, Jihye Kim, Guoliang Wang, Alicia Purkey, Todd M. Pitts, Anna Nguyen, Dexiang Gao, Patrick Blatchford, Anna Capasso, Alwin G. Schuller, S. Gail Eckhardt and John J. Arcaroli _

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Oncotarget. 2016; 7:28273-28285. https://doi.org/10.18632/oncotarget.8626

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Abstract

Kevin S. Quackenbush1, Stacey Bagby1, Wai Meng Tai1,2, Wells A. Messersmith1, Anna Schreiber1, Justin Greene1, Jihye Kim1, Guoliang Wang1, Alicia Purkey1, Todd M. Pitts1, Anna Nguyen1, Dexiang Gao1, Patrick Blatchford1, Anna Capasso1, Alwin G. Schuller3, S. Gail Eckhardt1, John J. Arcaroli1

1Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA

2Division of Medical Oncology, National Cancer Centre Singapore, Singapore

3AstraZeneca R & D Boston, Massachusetts, Waltham, Massachusetts, MA, USA

Correspondence to:

John J. Arcaroli, email: [email protected]

Keywords: CRC, WNT, IRN, NuMA, PDTX

Received: December 30, 2015     Accepted: February 28, 2016     Published: April 07, 2016

ABSTRACT

Background: Dysregulation of the canonical Wnt signaling pathway has been implicated in colorectal cancer (CRC) development as well as incipient stages of malignant transformation. In this study, we investigated the antitumor effects of AZ1366 (a novel tankyrase inhibitor) as a single agent and in combination with irinotecan in our patient derived CRC explant xenograft models.

Results: Six out of 18 CRC explants displayed a significant growth reduction to AZ1366. There was one CRC explant (CRC040) that reached the threshold of sensitivity (TGII ≤ 20%) in this study. In addition, the combination of AZ1366 + irinotecan demonstrated efficacy in 4 out of 18 CRC explants. Treatment effects on the WNT pathway revealed that tankyrase inhibition was ineffective at reducing WNT dependent signaling. However, the anti-tumor effects observed in this study were likely a result of alternative tankyrase effects whereby tankyrase inhibition reduced NuMA levels.

Materials and Methods: Eighteen CRC explants were treated with AZ1366 single agent or in combination for 28 days and treatment responses were assessed. Pharmacokinetic (AZ1366 drug concentrations) and pharmacodynamic effects (Axin2 levels) were investigated over 48 hours. Immunohistochemistry of nuclear β-catenin levels as well as western blot was employed to examine the treatment effects on the WNT pathway as well as NuMA.

Conclusions: Combination AZ1366 and irinotecan achieved greater anti-tumor effects compared to monotherapy. Activity was limited to CRC explants that displayed irinotecan resistance and increased protein levels of tankyrase and NuMA.


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