ArticleThyroid : official journal of the American Thyroid Association2013
The PLK1 inhibitor GSK461364A is effective in poorly differentiated and anaplastic thyroid carcinoma cells, independent of the nature of their driver mutations.
Article in Thyroid : official journal of the American Thyroid Association, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 31 citations in OpenAlex.
- Therapeutic inhibition of polo-like kinases in anaplastic thyroid cancer.Cancer science · 2021Article
- Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1.Journal of medicinal chemistry · 2020Article
- Review
- PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer.Cancer letters · 2018Article
- Therapeutic advances in anaplastic thyroid cancer: a current perspective.Molecular cancer · 2018Review
- Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer.Molecular cancer therapeutics · 2017Article
- Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis.Oncotarget · 2016Article
- Mouse models of thyroid cancer: A 2015 update.Molecular and cellular endocrinology · 2016Review
- PLK1 promotes epithelial-mesenchymal transition and metastasis of gastric carcinoma cells.American journal of translational research · 2016Article
- Plk1 inhibition enhances the efficacy of gemcitabine in human pancreatic cancer.Cell cycle (Georgetown, Tex.) · 2016Article
- Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy.Trends in pharmacological sciences · 2015Review
- Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer.Molecular and cellular biology · 2015Article
- Identification of thyroid tumor cell vulnerabilities through a siRNA-based functional screening.Oncotarget · 2015Article
- Modeling anaplastic thyroid carcinoma in the mouse.Hormones & cancer · 2015Review
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3 authors at 1 institution in 1 country.
Funding
Abstract
backgroundPoorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are the most aggressive forms of thyroid cancer. Despite their low incidence, they account for a disproportionate number of thyroid cancer-related deaths because of their resistance to most therapeutic approaches. We have generated mouse models that develop ATC ([Pten, p53](thyr-/-) mice) and follicular thyroid cancer with areas of poor differentiation (Pten(thyr-/-),Kras(G12D) mice). Comparative gene expression profiling of human and mouse ATCs reveals a common "mitotic signature" in which mitotic kinases, including Polo-like kinase-1 (PLK1), are found deregulated in both species. Most genes from this signature are also upregulated in poorly differentiated tumors developing in Pten(thyr-/-),Kras(G12D) mice. PLK1 is a crucial driving force for normal mitotic spindle formation, centrosome maturation, and separation, and its overexpression has been demonstrated in a wide range of tumors.
methodsHuman and mouse ATC and PDTC cell lines were treated with the PLK1 inhibitor GSK461364A, and proliferation, apoptosis, and mitotic spindle alterations were analyzed. Furthermore, immunocompetent mice were injected in the flank with mouse ATC cells, and treated with placebo or GSK461364A.
resultsWe show that the PLK1 inhibitor GSK461364A inhibits cell proliferation and induces cell death in both mouse ATC- and PDTC-derived cell lines and in several human ATC cell lines carrying different driver mutations. Dose-dependent changes in chromosome alignment and spindle assembly during mitosis are observed after treatment, together with changes in the mitotic index. FACS analysis reveals a G2/M phase arrest, followed by apoptosis, and mitotic slippage in cells with PI3K activation. GSK461364A is also effective in vivo, in an allograft model of ATC.
conclusionsTaken together, these data suggest that PLK1 targeting is a promising and effective therapeutic approach against PDTC cells and undifferentiated thyroid carcinoma cells.
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