Missing content? – Request curation!
Request curation for specific Genes, variants, or PubMed publications.
Have questions, comments or suggestions? - Let us know!
Email us at : email@example.com
|Ref Type||Journal Article|
|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|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|