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AMG 900, pan-Aurora kinase inhibitor, preferentially inhibits the proliferation of breast cancer cell lines with dysfunctional p53

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Abstract

Aurora kinases play important roles in cell division and are frequently overexpressed in human cancer. AMG 900 is a novel pan-Aurora kinase inhibitor currently being tested in Phase I clinical trials. We aimed to evaluate the in vitro activity of AMG 900 in a panel of 44 human breast cancer and immortalized cell lines and identify predictors of response. AMG 900 inhibited proliferation at low nanomolar concentrations in all cell lines tested. Response was further classified based on the induction of lethality. 25 cell lines were classified as highly sensitive (lethality at 10 nM of AMG 900 >10 %), 19 cell lines as less sensitive to AMG 900 (lethality at 10 nM of AMG 900 <10 %). Traditional molecular subtypes of breast cancer did not predict for this differential response. There was a weak association between AURKA amplification and response to AMG 900 (response ratio = 2.53, p = 0.09). mRNA expression levels of AURKA, AURKB, and AURKC and baseline protein levels of Aurora kinases A and B did not significantly associate with response. Cell lines with TP53 loss of function mutations (RR = 1.86, p = 0.004) and low baseline p21 protein levels (RR = 2.28, p = 0.0004) were far more likely to be classified as highly sensitive to AMG 900. AMG 900 induced p53 and p21 protein expression in cell lines with wt TP53. AMG 900 caused the accumulation of cells with >4 N DNA content in a majority of cell lines independently of sensitivity and p53 status. AMG 900 induced more pronounced apoptosis in highly sensitive p53-dysfunctional cell lines. We have found that AMG 900 is highly active in breast cancer cell lines and that TP53 loss of function mutations as well as low baseline expression of p21 protein predict strongly for increased sensitivity to this compound in vitro.

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Acknowledgments

We thank Marc Payton and Greg Friberg for their assistance on experimental design. We thank Eldri Undlien Due and Phuong Vu for their technical assistance. We thank Jiaying Zhuo for the editorial assistance. DJS received Department of Defense Innovator Award W81XWH-11-1-0104. The work was also funded by a gift to DJS by The Wittich Family Project for Emerging Therapies in Breast Cancer at UCLA’s Jonsson Comprehensive Cancer Center.

Conflict of interest

The study was funded in part by Amgen; stock ownership in Amgen (Judy Dering, Dennis J. Slamon), consultant/advisory role in Genentech, and Sanofi-Aventis (Dennis J. Slamon). Other authors have no conflict of interest.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 11-934 Factor Bldg, Los Angeles, CA, 90095, USA

    Ondrej Kalous, Dylan Conklin, Amrita J. Desai, Judy Dering, Jennifer Goldstein, Charles Ginther, Lee Anderson, Ming Lu, Teodora Kolarova, Mark A. Eckardt, Dennis J. Slamon & Richard S. Finn

  2. Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    Anita Langerød & Anne-Lise Børresen-Dale

  3. The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    Anne-Lise Børresen-Dale

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  1. Ondrej Kalous
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Correspondence to Richard S. Finn.

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Ondrej Kalous and Dylan Conklin have contributed equally to this work.

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Kalous, O., Conklin, D., Desai, A.J. et al. AMG 900, pan-Aurora kinase inhibitor, preferentially inhibits the proliferation of breast cancer cell lines with dysfunctional p53. Breast Cancer Res Treat 141, 397–408 (2013). https://doi.org/10.1007/s10549-013-2702-z

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