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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 Molecular cancer therapeutics
Vol 14
Issue 12
Date 2015 Dec
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 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
KW-2450 KW2450|KW 2450 Aurka Inhibitors 24 Aurkb Inhibitors 20 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
Unknown unknown triple-receptor negative breast cancer not applicable KW-2450 Preclinical Actionable In a preclinical study, KW-2450 inhibited the growth of triple-negative breast cancer cells in culture and in xenograft models (PMID: 26443806). 26443806
Unknown unknown breast cancer not applicable KW-2450 Preclinical Actionable In a preclinical study, KW-2450 inhibited growth of several breast cancer cell lines in culture, including ESR1 positive, ERBB2 (HER2) positive/ESR1 positive, ERBB2 (HER2) positive, and triple-negative subtypes (PMID: 26443806). 26443806
Unknown unknown triple-receptor negative breast cancer not applicable KW-2450 + Selumetinib Preclinical Actionable In a preclinical study, the combination of KW-2450 and Selumetinib worked synergistically to inhibit growth of triple-negative breast cancer cells in culture (PMID: 26443806). 26443806