Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells.

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Murai S, Matuszkiewicz J, Okuzono Y, Miya H, DE Jong R

Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells.

Anticancer Res. 2017 Feb;37(2):437-444. doi: 10.21873/anticanres.11335.

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28179288 [ View in PubMed

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Abstract

BACKGROUND: Aurora B kinase plays an essential role in chromosome segregation and cytokinesis, and is dysregulated in many cancer types, making it an attractive therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy in both in vitro and in vivo oncology models. MATERIALS AND METHODS: We conducted a synthetic lethal siRNA screening to identify the genes that, when silenced, can potentiate the cell growth-inhibitory effect of TAK-901. RESULTS: B-cell lymphoma-extra large (BCL-xL) depletion by siRNA or chemical inhibition synergized with TAK-901 in cancer cell lines. As a mechanism of synthetic lethality, active BCL2 associated X, apoptosis regulator (BAX) was induced by TAK-901. BCL-xL protected cells from BAX-dependent apoptosis induction. Therefore, TAK-901 sensitizes cancer cells to BCL-xL inhibition. CONCLUSION: Polyploid cells induced by TAK-901 are vulnerable to BCL-xL inhibition. Our findings may have an impact on combination strategies with aurora B inhibitors in clinical studies.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
TAK-901	Apoptosis regulator BAX	Protein	Humans	Unknown	Activator	Details
TAK-901	Aurora kinase B	Protein	Humans	Yes	Inhibitor	Details