Co-inhibition of polo-like kinase 1 and Aurora kinases promotes mitotic catastrophe

Oncotarget. 2015 Apr 20;6(11):9327-40. doi: 10.18632/oncotarget.3313.

Abstract

Mitosis is choreographed by a number of protein kinases including polo-like kinases and Aurora kinases. As these kinases are frequently dysregulated in cancers, small-molecule inhibitors have been developed for targeted anticancer therapies. Given that PLK1 and Aurora kinases possess both unique functions as well as co-regulate multiple mitotic events, whether pharmacological inhibition of these kinases together can enhance mitotic catastrophe remains an outstanding issue to be determined. Using concentrations of inhibitors that did not induce severe mitotic defects on their own, we found that both the metaphase arrest and mitotic slippage induced by inhibitors targeting Aurora A and Aurora B (MK-5108 and Barasertib respectively) were enhanced by a PLK1 inhibitor (BI 2536). We found that PLK1 is overexpressed in cells from nasopharyngeal carcinoma, a highly invasive cancer with poor prognosis, in comparison to normal nasopharyngeal epithelial cells. Nasopharyngeal carcinoma cells were more sensitive to BI 2536 as a single agent and co-inhibition with Aurora kinases than normal cells. These observations underscore the mechanism and potential benefits of targeting PLK1 and Aurora kinases to induce mitotic catastrophe in cancer cells.

Keywords: anticancer drugs; antimitotic drugs; kinases; mitosis; mitotic slippage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase B / antagonists & inhibitors*
  • Carcinoma
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Drug Synergism
  • Female
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitosis / drug effects*
  • Molecular Targeted Therapy
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / drug therapy
  • Nasopharyngeal Neoplasms / pathology
  • Organophosphates / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Pteridines / pharmacology*
  • Quinazolines / pharmacology*
  • Thiazoles / pharmacology*
  • Tumor Cells, Cultured

Substances

  • 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
  • 4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid
  • Antineoplastic Agents
  • BI 2536
  • Cell Cycle Proteins
  • Cyclohexanecarboxylic Acids
  • Organophosphates
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pteridines
  • Quinazolines
  • Thiazoles
  • Aurora Kinase A
  • Aurora Kinase B
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1