AMG 900, a small molecule inhibitor of aurora kinases, potentiates the activity of microtubule-targeting agents in human metastatic breast cancer models
Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer du sein triplement négatif, cette étude évalue l'activité antitumorale d'un composé par voie orale appelé AMG 900, seul ou en combinaison avec un inhibiteur de la fonction des microtubules (taxane ou épothilone)
Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer deaths, where 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 (MTAs) 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 Ser10, 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 (F11) (parental), MDA-MB-231 (F11) PTX-r (paclitaxel resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F11) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F11) PTX-r xenografts, in which >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 (MBC), and provide potential therapeutic options for patients with multidrug resistant tumors.
http://mct.aacrjournals.org/content/early/2013/08/29/1535-7163.MCT-12-1178.abstract