Small Molecule Therapeutics AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

Breast cancer is themost prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubuletargeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report,we investigate the activity ofAMG900alone and in combinationwith twodistinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibitedphosphorylationofhistoneH3onSer, aproximal substrate ofAurora-B, and inducedpolyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F; parental), MDA-MB-231 (F) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors. Mol Cancer Ther; 12(11); 2356–66. 2013 AACR.