Antitumor activity of KW-2450 against triple-negative breast cancer by inhibiting Aurora A and B kinases

Kazuharu Kai, Kimie Kondo, Xiaoping Wang, Xuemei Xie, Mary K. Pitner, Monica E. Reyes, Angie M. Torres-Adorno, Hiroko Masuda, Gabriel N. Hortobagyi, Chandra Bartholomeusz, Hideyuki Saya, Debu Tripathy, Subrata Sen, Naoto T. Ueno

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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.

Original languageEnglish
Pages (from-to)2687-2699
Number of pages13
JournalMolecular Cancer Therapeutics
Volume14
Issue number12
DOIs
Publication statusPublished - 2015 Dec 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kai, K., Kondo, K., Wang, X., Xie, X., Pitner, M. K., Reyes, M. E., Torres-Adorno, A. M., Masuda, H., Hortobagyi, G. N., Bartholomeusz, C., Saya, H., Tripathy, D., Sen, S., & Ueno, N. T. (2015). Antitumor activity of KW-2450 against triple-negative breast cancer by inhibiting Aurora A and B kinases. Molecular Cancer Therapeutics, 14(12), 2687-2699. https://doi.org/10.1158/1535-7163.MCT-15-0096