TY - JOUR
T1 - Antitumor activity of KW-2450 against triple-negative breast cancer by inhibiting Aurora A and B kinases
AU - Kai, Kazuharu
AU - Kondo, Kimie
AU - Wang, Xiaoping
AU - Xie, Xuemei
AU - Pitner, Mary K.
AU - Reyes, Monica E.
AU - Torres-Adorno, Angie M.
AU - Masuda, Hiroko
AU - Hortobagyi, Gabriel N.
AU - Bartholomeusz, Chandra
AU - Saya, Hideyuki
AU - Tripathy, Debu
AU - Sen, Subrata
AU - Ueno, Naoto T.
N1 - Funding Information:
The authors thank Dr. Jangsoon Lee, Dionysios N. Giannoukos, and Parth U. Sawhney for their help in animal experiments and Tamara K. Locke (The University of Texas MD Anderson Cancer Center) for her help in editing this article. This research was supported by Kyowa Hakko Kirin Co., Ltd. (Tokyo, Japan; to N.T. Ueno) and in part by the U.S. NIH/National Cancer Institute under award number P30CA016672 (to R.A. DePinho) and by the Nellie B. Connally Breast Cancer Research Fund (to D. Tripathy). K. Kai was supported by the program "Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation" by the Ministry of Education, Culture, Sports, Science and Technology, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958177285&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958177285&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-15-0096
DO - 10.1158/1535-7163.MCT-15-0096
M3 - Article
C2 - 26443806
AN - SCOPUS:84958177285
SN - 1535-7163
VL - 14
SP - 2687
EP - 2699
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -
