American Association for Cancer Research
15357163mct150096-sup-139412_1_supp_3106065_nt8qlg.pdf (378.64 kB)

Supplementary Figure 6 from Antitumor Activity of KW-2450 against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases

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journal contribution
posted on 2023-04-03, 14:06 authored by 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

Cell cycle profile in p53-wild breast cancer cells treated with KW-2450.



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. Mol Cancer Ther; 14(12); 2687–99. ©2015 AACR.