Inhibiting Aurora kinases reduces tumor growth and suppresses tumor recurrence after chemotherapy in patient-derived triple-negative breast cancer xenografts
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'intérêt d'un composé appelé AS703569, un inhibiteur de kinases Aurora, pour le traitement des cancers du sein triplement négatifs
Triple-negative breast cancers (TNBC) have an aggressive phenotype with a relatively high rate of recurrence and poor overall survival. To date, there is no approved targeted therapy for TNBC. Aurora kinases (AK) act as regulators of mammalian cell division. They are important for cell cycle progression and are frequently overexpressed or mutated in human tumors, including breast cancer. In this study we investigated the therapeutic potential of targeting AK in preclinical models of human breast cancers, using a pan- inhibitor of AK, AS703569. In vitro, AS703569 was tested in 15 human breast cancer cell lines. TNBC cell lines were more sensitive to AS703569 than were other types of breast cancer cells. Inhibition of proliferation was associated to cell-cycle arrest, aneuploidy and apoptosis. In vivo, AS703569 administered alone significantly inhibited tumor growth in 7 out of 11 patient-derived breast cancer xenografts. Treatment with AS703569 was associated to a decrease of phospho-histone H3 expression. Finally, AS703569 combined to doxorubicin-cyclophosphamide significantly inhibited in vivo tumor recurrence, suggesting that AK inhibitors could be used both in monotherapy and combination settings. In conclusions, these data indicate that targeting Aurora kinases could represent a new effective approach for TNBC treatment.
http://mct.aacrjournals.org/content/early/2012/09/25/1535-7163.MCT-12-0441-T.abstract