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

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Aurora Kinase B
Aurora Kinase A
Triple Negative Breast Neoplasms
Mitogen-Activated Protein Kinase Kinases
Apoptosis
Heterografts
Breast Neoplasms
Mitotic Index
Tetraploidy
Progesterone Receptors
KW-2450
Estrogen Receptors
Pharmaceutical Preparations
Cell Division
Agar
Cell Survival
Cell Cycle
Phosphotransferases
Phenotype

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Antitumor activity of KW-2450 against triple-negative breast cancer by inhibiting Aurora A and B kinases. / Kai, Kazuharu; Kondo, Kimie; Wang, Xiaoping; Xie, Xuemei; Pitner, Mary K.; Reyes, Monica E.; Torres-Adorno, Angie M.; Masuda, Hiroko; Hortobagyi, Gabriel N.; Bartholomeusz, Chandra; Saya, Hideyuki; Tripathy, Debu; Sen, Subrata; Ueno, Naoto T.

In: Molecular Cancer Therapeutics, Vol. 14, No. 12, 01.12.2015, p. 2687-2699.

Research output: Contribution to journalArticle

Kai, K, Kondo, K, Wang, X, Xie, X, Pitner, MK, Reyes, ME, Torres-Adorno, AM, Masuda, H, Hortobagyi, GN, Bartholomeusz, C, Saya, H, Tripathy, D, Sen, S & Ueno, NT 2015, 'Antitumor activity of KW-2450 against triple-negative breast cancer by inhibiting Aurora A and B kinases', Molecular Cancer Therapeutics, vol. 14, no. 12, pp. 2687-2699. https://doi.org/10.1158/1535-7163.MCT-15-0096
Kai, Kazuharu ; Kondo, Kimie ; Wang, Xiaoping ; Xie, Xuemei ; Pitner, Mary K. ; Reyes, Monica E. ; Torres-Adorno, Angie M. ; Masuda, Hiroko ; Hortobagyi, Gabriel N. ; Bartholomeusz, Chandra ; Saya, Hideyuki ; Tripathy, Debu ; Sen, Subrata ; Ueno, Naoto T. / Antitumor activity of KW-2450 against triple-negative breast cancer by inhibiting Aurora A and B kinases. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 12. pp. 2687-2699.
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AU - Pitner, Mary K.

AU - Reyes, Monica E.

AU - Torres-Adorno, Angie M.

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AU - Hortobagyi, Gabriel N.

AU - Bartholomeusz, Chandra

AU - Saya, Hideyuki

AU - Tripathy, Debu

AU - Sen, Subrata

AU - Ueno, Naoto T.

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