Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

Linda Vidarsdottir; Gudridur Steingrimsdottir; Sigridur Klara Bodvarsdottir; Helga Margret Ogmundsdottir; Jorunn Erla Eyfjord

doi:10.1007/s10637-010-9566-4

Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	425-434
Number of pages	10
Journal	Investigational New Drugs
Volume	30
Issue number	2
DOIs	https://doi.org/10.1007/s10637-010-9566-4
Publication status	Published - Apr 2012

Bibliographical note

Funding Information: The authors thank Margrét Steinarsdóttir at the Chromosome Laboratory, Department of Genetics and Molecular Medicine at Landspitali National University Hospital for cytogenetic analysis and Cheryl M. Lewis and David M. Euhus (Hamond Center for Therapeutic Oncology Research and Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, USA) for providing 348T, 348KT, 2980T, 2981T, 1585T, 1585KT and 3736T cell lines (Hamond Center for Therapeutic Oncology Research and Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, USA). This work was supported by the Icelandic Research Fund for graduate students (L. Vidarsdottir), the University of Iceland Research Fund, Gongum saman and the Icelandic Science Foundation (RANNIS).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Other keywords

Aurora kinase
BRCA2
Breast cancer
Inhibitor
p53

Access to Document

10.1007/s10637-010-9566-4

Cite this

@article{1a0ddf01594b4e4cae2254b26b819ef2,

title = "Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition",

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.",

keywords = "Aurora kinase, BRCA2, Breast cancer, Inhibitor, p53",

author = "Linda Vidarsdottir and Gudridur Steingrimsdottir and Bodvarsdottir, \{Sigridur Klara\} and Ogmundsdottir, \{Helga Margret\} and Eyfjord, \{Jorunn Erla\}",

note = "Funding Information: The authors thank Margr{\'e}t Steinarsd{\'o}ttir at the Chromosome Laboratory, Department of Genetics and Molecular Medicine at Landspitali National University Hospital for cytogenetic analysis and Cheryl M. Lewis and David M. Euhus (Hamond Center for Therapeutic Oncology Research and Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, USA) for providing 348T, 348KT, 2980T, 2981T, 1585T, 1585KT and 3736T cell lines (Hamond Center for Therapeutic Oncology Research and Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, USA). This work was supported by the Icelandic Research Fund for graduate students (L. Vidarsdottir), the University of Iceland Research Fund, Gongum saman and the Icelandic Science Foundation (RANNIS).",

year = "2012",

month = apr,

doi = "10.1007/s10637-010-9566-4",

language = "English",

volume = "30",

pages = "425--434",

journal = "Investigational New Drugs",

issn = "0167-6997",

publisher = "Springer",

number = "2",

}

TY - JOUR

T1 - Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

AU - Vidarsdottir, Linda

AU - Steingrimsdottir, Gudridur

AU - Bodvarsdottir, Sigridur Klara

AU - Ogmundsdottir, Helga Margret

AU - Eyfjord, Jorunn Erla

N1 - Funding Information: The authors thank Margrét Steinarsdóttir at the Chromosome Laboratory, Department of Genetics and Molecular Medicine at Landspitali National University Hospital for cytogenetic analysis and Cheryl M. Lewis and David M. Euhus (Hamond Center for Therapeutic Oncology Research and Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, USA) for providing 348T, 348KT, 2980T, 2981T, 1585T, 1585KT and 3736T cell lines (Hamond Center for Therapeutic Oncology Research and Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, USA). This work was supported by the Icelandic Research Fund for graduate students (L. Vidarsdottir), the University of Iceland Research Fund, Gongum saman and the Icelandic Science Foundation (RANNIS).

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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.

KW - Aurora kinase

KW - BRCA2

KW - Breast cancer

KW - Inhibitor

KW - p53

UR - https://www.scopus.com/pages/publications/84862247462

U2 - 10.1007/s10637-010-9566-4

DO - 10.1007/s10637-010-9566-4

M3 - Article

C2 - 20960027

SN - 0167-6997

VL - 30

SP - 425

EP - 434

JO - Investigational New Drugs

JF - Investigational New Drugs

IS - 2

ER -

Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

Abstract

Bibliographical note

UN SDGs

Other keywords

Access to Document

Fingerprint

Cite this