Predictive biomarkers of sensitivity to the Aurora and angiogenic kinase inhibitor ENMD-2076 in preclinical breast cancer models

Jennifer R. Diamond, S. Gail Eckhardt, Aik Choon Tan, Timothy P. Newton, Heather M. Selby, Kelsey L. Brunkow, Maria I. Kachaeva, Marileila Varella-Garcia, Todd M. Pitts, Mark R. Bray, Graham C. Fletcher, John J. Tentler

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31 Citations (Scopus)

Abstract

Purpose: The Aurora kinases are a family of conserved serine-threonine kinases with key roles in mitotic cell division. As with other promising anticancer targets, patient selection strategies to identify a responsive subtype will likely be required for successful clinical development of Aurora kinase inhibitors. The purpose of this study was to evaluate the antitumor activity of the Aurora and angiogenic kinase inhibitor ENMD-2076 against preclinical models of breast cancer with identification of candidate predictive biomarkers. Experimental Design: Twenty-nine breast cancer cell lines were exposed to ENMD-2076 and the effects on proliferation, apoptosis, and cell-cycle distribution were evaluated. In vitro activity was confirmed in MDA-MB-468 and MDA-MB-231 triple-negative breast cancer xenografts. Systematic gene expression analysis was used to identify up- and downregulated pathways in the sensitive and resistant cell lines, including within the triple-negative breast cancer subset. Results: ENMD-2076 showed antiproliferative activity against breast cancer cell lines, with more robust activity against cell lines lacking estrogen receptor expression and those without increased HER2 expression. Within the triple-negative breast cancer subset, cell lines with a p53 mutation and increased p53 expression were more sensitive to the cytotoxic and proapoptotic effects of ENMD-2076 exposure than cell lines with decreased p53 expression. Conclusions: ENMD-2076 exhibited robust anticancer activity against models of triple-negative breast cancer and the candidate predictive biomarkers identified in this study may be useful in selecting patients for Aurora kinase inhibitors in the future.

Original languageEnglish
Pages (from-to)291-303
Number of pages13
JournalClinical Cancer Research
Volume19
Issue number1
DOIs
Publication statusPublished - 2013 Jan 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Diamond, J. R., Eckhardt, S. G., Tan, A. C., Newton, T. P., Selby, H. M., Brunkow, K. L., Kachaeva, M. I., Varella-Garcia, M., Pitts, T. M., Bray, M. R., Fletcher, G. C., & Tentler, J. J. (2013). Predictive biomarkers of sensitivity to the Aurora and angiogenic kinase inhibitor ENMD-2076 in preclinical breast cancer models. Clinical Cancer Research, 19(1), 291-303. https://doi.org/10.1158/1078-0432.CCR-12-1611