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

1 Citation (Scopus)

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.

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

Fingerprint

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

  • Genetics
  • Oncology
  • 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; Gail Eckhardt, S.; 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, Gail Eckhardt, S & 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 ; Gail Eckhardt, S. ; 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.
@article{605c831679f14091b6379a0dd17a5475,
title = "Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer",
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.",
keywords = "Colorectal cancer, Patient-derived xenograft, Plk1, TAK-960",
author = "Klauck, {Peter J.} and Bagby, {Stacey M.} and Anna Capasso and Bradshaw-Pierce, {Erica L.} and Selby, {Heather M.} and Anna Spreafico and Tentler, {John J.} and Tan, {Aik Choon} and Jihye Kim and Arcaroli, {John J.} and Alicia Purkey and Messersmith, {Wells A.} and Keisuke Kuida and {Gail Eckhardt}, S. and Pitts, {Todd M.}",
year = "2018",
month = "2",
day = "5",
doi = "10.1186/s12885-018-4036-z",
language = "English (US)",
volume = "18",
journal = "BMC Cancer",
issn = "1471-2407",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer

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 - Gail Eckhardt, S.

AU - Pitts, Todd M.

PY - 2018/2/5

Y1 - 2018/2/5

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.

KW - Colorectal cancer

KW - Patient-derived xenograft

KW - Plk1

KW - TAK-960

UR - http://www.scopus.com/inward/record.url?scp=85041425856&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041425856&partnerID=8YFLogxK

U2 - 10.1186/s12885-018-4036-z

DO - 10.1186/s12885-018-4036-z

M3 - Article

C2 - 29402316

AN - SCOPUS:85041425856

VL - 18

JO - BMC Cancer

JF - BMC Cancer

SN - 1471-2407

IS - 1

M1 - 136

ER -