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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer

Authors: Peter J. Klauck, Stacey M. Bagby, Anna Capasso, Erica L. Bradshaw-Pierce, Heather M. Selby, Anna Spreafico, John J. Tentler, Aik Choon Tan, Jihye Kim, John J. Arcaroli, Alicia Purkey, Wells A. Messersmith, Keisuke Kuida, S. Gail Eckhardt, Todd M. Pitts

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Polo-like kinase 1 (Plk1) is a serine/threonine kinase that is a key regulator of multiple stages of mitotic progression. Plk1 is upregulated in many tumor types including colorectal cancer (CRC) and portends a poor prognosis. TAK-960 is an ATP-competitive Plk1 inhibitor that has demonstrated efficacy across a broad range of cancer cell lines, including CRC. In this study, we investigated the activity of TAK-960 against a large collection of CRC models including 55 cell lines and 18 patient-derived xenografts.

Methods

Fifty-five CRC cell lines and 18 PDX models were exposed to TAK-960 and evaluated for proliferation (IC50) and Tumor Growth Inhibition Index, respectively. Additionally, 2 KRAS wild type and 2 KRAS mutant PDX models were treated with TAK-960 as single agent or in combination with cetuximab or irinotecan. TAK-960 mechanism of action was elucidated through immunoblotting and cell cycle analysis.

Results

CRC cell lines demonstrated a variable anti-proliferative response to TAK-960 with IC50 values ranging from 0.001 to > 0.75 μmol/L. Anti-proliferative effects were sustained after removal of drug. Following TAK-960 treatment a highly variable accumulation of mitotic (indicating cell cycle arrest) and apoptotic markers was observed. Cell cycle analysis demonstrated that TAK-960 treatment induced G2/M arrest and polyploidy. Six out of the eighteen PDX models responded to single agent TAK-960 therapy (TGII< 20). The addition of TAK-960 to standard of care chemotherapy resulted in largely additive antitumor effects.

Conclusion

TAK-960 is an active anti-proliferative agent against CRC cell lines and PDX models. Collectively, these data suggest that TAK-960 may be of therapeutic benefit alone or in combination with other agents, although future work should focus on the development of predictive biomarkers and hypothesis-driven rational combinations.
Appendix
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Metadata
Title
Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer
Authors
Peter J. Klauck
Stacey M. Bagby
Anna Capasso
Erica L. Bradshaw-Pierce
Heather M. Selby
Anna Spreafico
John J. Tentler
Aik Choon Tan
Jihye Kim
John J. Arcaroli
Alicia Purkey
Wells A. Messersmith
Keisuke Kuida
S. Gail Eckhardt
Todd M. Pitts
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4036-z

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