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Ref Type Journal Article
PMID (23990115)
Authors Bush TL, Payton M, Heller S, Chung G, Hanestad K, Rottman JB, Loberg R, Friberg G, Kendall RL, Saffran D, Radinsky R
Title AMG 900, a small-molecule inhibitor of aurora kinases, potentiates the activity of microtubule-targeting agents in human metastatic breast cancer models.
Journal Molecular cancer therapeutics
Vol 12
Issue 11
Date 2013 Nov
URL
Abstract Text Breast cancer is the most 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 microtubule-targeting 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 of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B, and induced polyploidy 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(11); parental), MDA-MB-231 (F(11)) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F(11)) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F(11)) 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown triple-receptor negative breast cancer not applicable AMG 900 Preclinical - Cell line xenograft Actionable In a preclinical study, AMG 900 induced apoptosis in triple-negative breast cancer (TNBC) cell lines in culture and inhibited tumor growth in TNBC cell line xenograft models (PMID: 23990115). 23990115
Unknown unknown triple-receptor negative breast cancer not applicable AMG 900 + Ixabepilone Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of AMG 900 and Ixempra (ixabepilone) resulted in tumor regression in triple-negative breast cancer cell line xenograft models (PMID: 23990115). 23990115