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

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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 12 Pg. 2687-99 (Dec 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 26443806 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• AZD 6244
• Benzimidazoles
• Indazoles
• KW-2450
• Piperazines
• Protein Kinase Inhibitors
• AURKB protein, human
• Aurora Kinase A
• Aurora Kinase B

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Apoptosis (drug effects)
• Aurora Kinase A (antagonists & inhibitors, genetics)
• Aurora Kinase B (antagonists & inhibitors, genetics)
• Benzimidazoles (administration & dosage)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Indazoles (administration & dosage)
• Mice
• Piperazines (administration & dosage)
• Protein Kinase Inhibitors (administration & dosage)
• Triple Negative Breast Neoplasms (drug therapy, genetics, pathology)
• Xenograft Model Antitumor Assays