Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

Summary 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...

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Bibliographic Details
Published in:	Investigational new drugs Vol. 30; no. 2; pp. 425 - 434
Main Authors:	Vidarsdottir, Linda, Steingrimsdottir, Gudridur, Bodvarsdottir, Sigridur Klara, Ogmundsdottir, Helga Margret, Eyfjord, Jorunn Erla
Format:	Journal Article
Language:	English
Published:	Boston Springer US 01-04-2012 Springer Nature B.V
Subjects:	Antineoplastic Agents - pharmacology Apoptosis Aurora Kinases Benzamides - pharmacology Binding sites BRCA2 Protein - genetics Breast cancer Breast Neoplasms - enzymology Breast Neoplasms - genetics Breast Neoplasms - pathology Cancer therapies Cell cycle Cell Death - drug effects Cell division Cell Line, Tumor Cell Size - drug effects Cell Survival - drug effects Chromosomes Clinical trials Cytokinesis - drug effects DNA damage Dose-Response Relationship, Drug Drugs Female Humans Inhibitor drugs Inhibitory Concentration 50 Kinases Laboratories Medical research Medicine Medicine & Public Health Mitosis - drug effects Molecular Targeted Therapy Mutation Oncology Pancreatic Neoplasms - enzymology Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Pharmacology/Toxicology Ploidies Polyploidy Preclinical Studies 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 Studies Transfection Tumor Suppressor Protein p53 - genetics Tumors Iceland Inhibitor Aurora kinase Breast cancer BRCA2 p53
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Summary:	Summary 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.
ISSN:	0167-6997 1573-0646
DOI:	10.1007/s10637-010-9566-4