title: Antitumor Activity of KW-2450 against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases.
abstract: Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and, because Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of KW-2450, a multikinase inhibitor of both Aurora A and B kinases. We observed significant inhibitory activities of KW-2450 on cell viability, apoptosis, colony formation in agar, and mammosphere formation in TNBC cells. The growth of TNBC xenografts was significantly inhibited with KW-2450. In cell-cycle analysis, KW-2450 induced tetraploid accumulation followed by apoptosis or surviving octaploid (8N) cells, depending on dose. These phenotypes resembled those of Aurora B knockdown and complete pharmaceutical inhibition of Aurora A. We demonstrated that 8N cells resulting from KW-2450 treatment depended on the activation of mitogen-activated protein kinase kinase (MEK) for their survival. When treated with the MEK inhibitor selumetinib combined with KW-2450, compared with KW-2450 alone, the 8N cell population was significantly reduced and apoptosis was increased. Indeed, this combination showed synergistic antitumor effect in SUM149 TNBC xenografts. Collectively, Aurora A and B inhibition had a significant antitumor effect against TNBC, and this antitumor effect was maximized by the combination of selumetinib with Aurora A and B inhibition.
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. nueno@mdanderson.org kkai@mdanderson.org.
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Kai
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kimie
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Xie
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Pitner
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Reyes
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Angie M
authors.initials: AM
authors.lastname: Torres-Adorno
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Masuda
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chandra
authors.initials: C
authors.lastname: Bartholomeusz
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Debu
authors.initials: D
authors.lastname: Tripathy
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. nueno@mdanderson.org kkai@mdanderson.org.
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000235:genetics; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000235:genetics; D001562:Benzimidazoles / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D007191:Indazoles; C000610672:KW-2450; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C576921:AURKB protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B