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Updated: Jun 7, 2026
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition
Linda Vidarsdottir1, Gudridur Steingrimsdottir, Sigridur Klara Bodvarsdottir
1Cancer Research Laboratory, Biomedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
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.
Insights
Aurora kinase inhibitors show promise for cancer treatment, but sensitivity varies. Researchers found that BRCA2-mutated tumors with high Aurora expression and p53 defects are most sensitive to these inhibitors.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Therapeutics
Background:
- Aurora kinases (A and B) are crucial for mitosis and cell division.
- Aberrant expression of Aurora kinases is linked to various cancers.
- Aurora kinase inhibitors are under clinical investigation for cancer treatment.
Purpose of the Study:
- To investigate the sensitivity of epithelial cell lines to the Aurora kinase inhibitor ZM447439.
- To identify predictive markers for sensitivity to Aurora inhibition, focusing on BRCA2 and p53 status and Aurora kinase expression levels.
Main Methods:
- Testing ZM447439 sensitivity on 15 non-malignant and malignant epithelial cell lines.
- Analyzing cell lines for BRCA2 and p53 status and Aurora kinase expression (mRNA).
- Assessing cell survival (IC50 values), mitosis, and cytokinesis following inhibitor treatment.
Main Results:
- Sensitivity to ZM447439 varied, not directly correlating with BRCA2 mutation status or Aurora-A/B mRNA levels alone.
- Aurora-A and -B expression levels correlated with each other.
- Inhibitor treatment caused mitotic completion but inhibited cytokinesis, leading to polyploidy and multinucleation, with p53 defects not fully explaining polyploidy levels.
Conclusions:
- BRCA2-mutated cells exhibit variable sensitivity to Aurora kinase inhibition.
- Predicting sensitivity requires more than just Aurora expression levels; a combination of factors is key.
- BRCA2-mutated tumors with high Aurora expression and defective p53 are potential candidates for Aurora inhibitor therapy.
