The PLK1 inhibitor GSK461364A is effective in poorly differentiated and anaplastic thyroid carcinoma cells, independent of the nature of their driver mutations

Thyroid. 2013 Oct;23(10):1284-93. doi: 10.1089/thy.2013.0037. Epub 2013 Jul 25.

Abstract

Background: Poorly 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.

Methods: Human 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.

Results: We 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.

Conclusions: Taken together, these data suggest that PLK1 targeting is a promising and effective therapeutic approach against PDTC cells and undifferentiated thyroid carcinoma cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma / drug therapy*
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carcinoma / pathology
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Cell Dedifferentiation
  • Cell Line, Tumor
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Mutation*
  • Neoplasm Transplantation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Random Allocation
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use*
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology
  • Tumor Burden / drug effects
  • ras Proteins / genetics*
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • GSK 461364A
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Thiophenes
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • ras Proteins