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

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 1 Pg. 291-303 (Jan 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23136197 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• ENMD 2076
• Pyrazoles
• Pyrimidines
• Tumor Suppressor Protein p53
• Receptor, ErbB-2
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Apoptosis (drug effects)
• Aurora Kinases
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cellular Senescence (drug effects)
• Cluster Analysis
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Profiling
• Humans
• Inhibitory Concentration 50
• Mice
• Mice, Nude
• Mutation
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyrazoles (pharmacology, toxicity)
• Pyrimidines (pharmacology, toxicity)
• Receptor, ErbB-2 (metabolism)
• Signal Transduction
• Tumor Stem Cell Assay
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays