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

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

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Article number136
JournalBMC Cancer
Volume18
Issue number1
DOIs
StatePublished - Feb 5 2018

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Colorectal Neoplasms
Phosphotransferases
Cell Line
irinotecan
Inhibitory Concentration 50
4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido(4,5-b)(1,4)diazepin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide
Cell Cycle
Neoplasms
Polyploidy
Protein-Serine-Threonine Kinases
Therapeutics
Standard of Care
Cell Cycle Checkpoints
Immunoblotting
Heterografts
Adenosine Triphosphate
Biomarkers
Drug Therapy
Growth

Keywords

  • Colorectal cancer
  • Patient-derived xenograft
  • Plk1
  • TAK-960

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Klauck, P. J., Bagby, S. M., Capasso, A., Bradshaw-Pierce, E. L., Selby, H. M., Spreafico, A., ... Pitts, T. M. (2018). Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer. BMC Cancer, 18(1), [136]. https://doi.org/10.1186/s12885-018-4036-z

Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer. / Klauck, Peter J.; Bagby, Stacey M.; Capasso, Anna; Bradshaw-Pierce, Erica L.; Selby, Heather M.; Spreafico, Anna; Tentler, John J.; Tan, Aik Choon; Kim, Jihye; Arcaroli, John J.; Purkey, Alicia; Messersmith, Wells A.; Kuida, Keisuke; Eckhardt, S Gail; Pitts, Todd M.

In: BMC Cancer, Vol. 18, No. 1, 136, 05.02.2018.

Research output: Contribution to journalArticle

Klauck, PJ, Bagby, SM, Capasso, A, Bradshaw-Pierce, EL, Selby, HM, Spreafico, A, Tentler, JJ, Tan, AC, Kim, J, Arcaroli, JJ, Purkey, A, Messersmith, WA, Kuida, K, Eckhardt, SG & Pitts, TM 2018, 'Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer' BMC Cancer, vol. 18, no. 1, 136. https://doi.org/10.1186/s12885-018-4036-z
Klauck, Peter J. ; Bagby, Stacey M. ; Capasso, Anna ; Bradshaw-Pierce, Erica L. ; Selby, Heather M. ; Spreafico, Anna ; Tentler, John J. ; Tan, Aik Choon ; Kim, Jihye ; Arcaroli, John J. ; Purkey, Alicia ; Messersmith, Wells A. ; Kuida, Keisuke ; Eckhardt, S Gail ; Pitts, Todd M. / Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer. In: BMC Cancer. 2018 ; Vol. 18, No. 1.
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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.",
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AU - Klauck, Peter J.

AU - Bagby, Stacey M.

AU - Capasso, Anna

AU - Bradshaw-Pierce, Erica L.

AU - Selby, Heather M.

AU - Spreafico, Anna

AU - Tentler, John J.

AU - Tan, Aik Choon

AU - Kim, Jihye

AU - Arcaroli, John J.

AU - Purkey, Alicia

AU - Messersmith, Wells A.

AU - Kuida, Keisuke

AU - Eckhardt, S Gail

AU - Pitts, Todd M.

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N2 - 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.

AB - 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.

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KW - Patient-derived xenograft

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