Abstract 3556: Antitumor activity of AMG 900, an orally available small molecule inhibitor of aurora kinases, alone and in combination with tubulin-targeting agents in human metastatic breast cancer
Authors: Bush Tammy L. , Heller Scott , Chung Grace , Guyot Deborah , Kendall Richard , Friberg Greg , Radinsky Robert , Payton Marc 
Published: June 2012

Background: Breast cancer is a heterogeneous disease that can be classified into distinct subtypes. The breast cancer subtype that lacks expression of hormone receptors (ER and PR) is characterized by its aggressive and metastatic nature. Tubulin-targeting agents are among the most active agents for the treatment of metastatic breast cancer (MBC). However, treatment of MBC frequently fails because of de novo or acquired resistance to taxanes. Consequently, there is an urgent need for novel therapeutics and combination strategies to effectively treat multidrug-resistant MBC. Recently, we reported the development of AMG 900, a novel ATP competitive small molecule inhibitor that is potent and selective for aurora-A, -B, and -C kinases. AMG 900 inhibits the proliferation of tumor cell lines and growth of multiple human xenografts, including taxane-resistant models. AMG 900 is currently in early clinical testing in advanced cancers.

Objective: To evaluate the effectiveness of AMG 900 alone and in combination with two different classes of tubulin-targeting agents (taxanes and epothilones) in human MDA-MB-231 (parental and taxane-resistant subline) MBC cell lines and xenografts.

Results: The MDA-MB-231 parental cell line is tumorigenic and metastatic in vivo. To establish the taxane-resistant cell line, MDA-MB-231-PTX-r, MDA-MB-231 parental cells were adapted to grow in the presence of increasing concentrations of paclitaxel. In vitro, AMG 900 induced polyploidy and inhibited colony growth of both MDA-MB-231 and MDA-MB-231-PTX-r cell lines. In combination, AMG 900 enhanced the effects of both paclitaxel and ixabepilone in a cell growth assay using MDA-MB-231 and MDA-MB-231-PTX-r cell lines, respectively. In tumor-bearing mice, AMG 900 blocked the phosphorylation of histone H3 and significantly inhibited the growth of both MDA-MB-231 and MDA-MB-231-PTX-r xenografts (&gt;70% inhibition; p &lt; 0.0002). To examine the effects of AMG 900 in combination with tubulin-targeting agents, mice were administered either docetaxel or ixabepilone (day 1) followed by AMG 900 (day 2 and 3). AMG 900 plus docetaxel resulted in enhanced efficacy in the MDA-MB-231 xenografts compared to either single agent (p &lt; 0.0006). Notably, AMG 900 plus ixabepilone resulted in tumor regressions in the MDA-MB-231-PTX-r xenografts compared to either single agent (p &lt; 0.0001). Histological analysis of the MDA-MB-231-PTX-r tumors revealed a pronounced increase in multinucleated cells after combined treatment with AMG 900 and ixabepilone compared to either single agent.

Conclusion: AMG 900, alone or in combination with tubulin-targeting agents such as ixabepilone, has the potential to treat multidrug resistant metastatic breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3556. doi:10.1158/1538-7445.AM2011-3556