Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

Invest New Drugs. 2012 Apr;30(2):425-34. doi: 10.1007/s10637-010-9566-4. Epub 2010 Oct 20.

Abstract

Aurora kinases play a vital part in successful mitosis and cell division. Aberrant Aurora-A and -B expression is commonly seen in various types of tumors. Small molecule Aurora inhibitors have already entered clinical trials. Aurora-A amplification has been shown to be associated with breast tumors from BRCA2-mutation carriers and such patients might therefore be candidates for treatment with Aurora kinase inhibitors. There is a need to identify markers that can predict sensitivity to Aurora inhibition. In this study sensitivity to the inhibitor ZM447439 was tested on a panel of 15 non-malignant and malignant epithelial cell lines that differed with respect to BRCA2 and p53 status and related to level of Aurora kinase expression. The IC(50) value for cell survival ranged from 1.9-8.1 μM and was not related to presence or absence of BRCA2 mutation. The levels of Aurora-A and -B expression correlated with each other but sensitivity towards ZM447439 did not correlate with levels of Aurora-A and -B mRNA expression, alone. Cells treated with the Aurora kinase inhibitor completed mitosis but cytokinesis was inhibited resulting in polyploidy and multinucleation. Different levels of polyploidy could not be fully explained by defects in p53. Only cell lines with a combination of high Aurora-A and -B expression, BRCA2 mutation and p53 defects showed more sensitivity towards Aurora inhibition than other cell lines. In conclusion, BRCA2-mutated cells showed variable sensitivity towards Aurora kinase inhibition. The level of sensitivity could not be predicted by Aurora expression levels alone but BRCA2 mutated tumors with high Aurora expression and non-functional p53 are likely candidates for treatment with Aurora inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Aurora Kinases
  • BRCA2 Protein / genetics*
  • Benzamides / pharmacology*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Size / drug effects
  • Cell Survival / drug effects
  • Cytokinesis / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Mitosis / drug effects
  • Molecular Targeted Therapy
  • Mutation*
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Ploidies
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Quinazolines / pharmacology*
  • RNA, Messenger / metabolism
  • Transfection
  • Tumor Suppressor Protein p53 / genetics

Substances

  • 4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline
  • Antineoplastic Agents
  • BRCA2 Protein
  • BRCA2 protein, human
  • Benzamides
  • Protein Kinase Inhibitors
  • Quinazolines
  • RNA, Messenger
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases