Therapeutic inhibition of polo-like kinases in anaplastic thyroid cancer

Cancer Sci. 2021 Feb;112(2):803-814. doi: 10.1111/cas.14769. Epub 2021 Jan 2.

Abstract

Polo-like kinases (PLKs) are potent regulators of cell proliferation and cell survival. Polo-like kinases are potential targets in the treatment of anaplastic thyroid cancer (ATC), a rare but deadly disease. The therapeutic effects of volasertib, a PLK inhibitor, was evaluated for the treatment of ATC either alone or in combination with sorafenib. Volasertib decreased cell viability in three ATC cell lines (8505C, 8305C, and KAT18) in a dose-dependent manner. Volasertib caused ATC cells to accumulate in G2 /M phase, activated caspase-3 activity, and induced apoptosis. Combination therapy using volasertib and sorafenib in ATC cells showed mostly synergistic effects. In vivo studies revealed that combination therapy of volasertib and sorafenib was effective in the treatment of 8505C xenografts. Single-agent volasertib treatment was sufficient to retard 8305C tumor growth. No substantial morbidity was observed in animals that received either single-agent or combination treatment. These preclinical findings suggest that volasertib could be an effective drug in treating ATC.

Keywords: anaplastic thyroid cancer; combination therapy; polo-like kinase; sorafenib; volasertib.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Humans
  • Mice
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Pteridines / pharmacology*
  • Thyroid Carcinoma, Anaplastic / pathology*
  • Thyroid Neoplasms / pathology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • BI 6727
  • Pteridines
  • Protein-Serine-Threonine Kinases