title: AMG 900, a small-molecule inhibitor of aurora kinases, potentiates the activity of microtubule-targeting agents in human metastatic breast cancer models.
abstract: 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.
authors.affiliation: Corresponding Author: Tammy L. Bush, Amgen Inc., 360 Binney Street, Mailstop 7-G-12, Cambridge, MA 02142. tbush@amgen.com.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Bush
authors.forename: Marc
authors.initials: M
authors.lastname: Payton
authors.forename: Scott
authors.initials: S
authors.lastname: Heller
authors.forename: Grace
authors.initials: G
authors.lastname: Chung
authors.forename: Kelly
authors.initials: K
authors.lastname: Hanestad
authors.forename: James B
authors.initials: JB
authors.lastname: Rottman
authors.forename: Robert
authors.initials: R
authors.lastname: Loberg
authors.forename: Gregory
authors.initials: G
authors.lastname: Friberg
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kendall
authors.forename: Douglas
authors.initials: D
authors.lastname: Saffran
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D034261:Epothilones / Q000494:pharmacology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000494:pharmacology*; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D050257:Tubulin Modulators / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; C555658:N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D050257:Tubulin Modulators; D064127:Aurora Kinases; C430592:ixabepilone; D017239:Paclitaxel