title: Inhibiting aurora kinases reduces tumor growth and suppresses tumor recurrence after chemotherapy in patient-derived triple-negative breast cancer xenografts.
abstract: 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 TNBCs. Aurora kinases 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 Aurora kinases in preclinical models of human breast cancers using a pan-inhibitor of Aurora kinases, 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 with cell-cycle arrest, aneuploidy, and apoptosis. In vivo, AS703569 administered alone significantly inhibited tumor growth in seven of 11 patient-derived breast cancer xenografts. Treatment with AS703569 was associated with a decrease of phospho-histone H3 expression. Finally, AS703569 combined to doxorubicin-cyclophosphamide significantly inhibited in vivo tumor recurrence, suggesting that Aurora kinase inhibitors could be used both in monotherapy and in combination settings. In conclusion, these data indicate that targeting Aurora kinases could represent a new effective approach for TNBC treatment.
authors.affiliation: EMD Serono Research Institute, Billerica, Massachusetts, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Romanelli
authors.forename: Anderson
authors.initials: A
authors.lastname: Clark
authors.forename: Franck
authors.initials: F
authors.lastname: Assayag
authors.forename: Sophie
authors.initials: S
authors.lastname: Chateau-Joubert
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Poupon
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Servely
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fontaine
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liu
authors.forename: Edward
authors.initials: E
authors.lastname: Spooner
authors.forename: Samantha
authors.initials: S
authors.lastname: Goodstal
authors.forename: Patricia
authors.initials: P
authors.lastname: de Cremoux
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases