Title |
Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer
|
---|---|
Published in |
BMC Cancer, February 2018
|
DOI | 10.1186/s12885-018-4036-z |
Pubmed ID | |
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 |
Abstract |
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. 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. 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. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 2 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 32 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Bachelor | 7 | 22% |
Researcher | 6 | 19% |
Student > Ph. D. Student | 4 | 13% |
Other | 2 | 6% |
Unspecified | 2 | 6% |
Other | 6 | 19% |
Unknown | 5 | 16% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 7 | 22% |
Biochemistry, Genetics and Molecular Biology | 7 | 22% |
Agricultural and Biological Sciences | 3 | 9% |
Unspecified | 2 | 6% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 3% |
Other | 4 | 13% |
Unknown | 8 | 25% |