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

• Published in: Anticancer research 2017-02, Vol.37 (2), p.437-444
• Main Authors: Murai, Saomi, Matuszkiewicz, Jennifer, Okuzono, Yuumi, Miya, Hiroyuki, DE Jong, Ron
• Format: Article
• Language: English
• Subjects: Aurora Kinase B - antagonists & inhibitors; bcl-2-Associated X Protein - biosynthesis; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - genetics; Carbolines - pharmacology; Cell Line, Tumor; Drug Synergism; Gene Knockdown Techniques; HCT116 Cells; HT29 Cells; Humans; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - therapy; Protein Kinase Inhibitors - pharmacology; RNA, Small Interfering - genetics; Sulfones - pharmacology; Transfection
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.11335

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. We conducted a synthetic lethal siRNA screening to identify the genes that, when silenced, can potentiate the cell growth-inhibitory effect of TAK-901. 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. 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.