Reference Detail

Ref Type

Journal Article

PMID

(26443806)

Authors

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

Title

Antitumor Activity of KW-2450 against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	12	2015 Dec	2687-99	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
KW-2450	KW-2450	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
KW-2450		KW2450\|KW 2450	Aurka Inhibitors 26 Aurkb Inhibitors 21 IGF-1R Inhibitor 17	KW-2450 is a multitargeted kinase inhibitor with activity against Aurora A and B, and IGF-1R, which potentially results in decreased tumor cell growth (PMID: 26443806, PMID: 30083253).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References