Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells.
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.
Pharmacology Research Laboratory II, Pharmaceutical Research Laboratories, Takeda Pharmaceutical Company Ltd., Kanagawa, Japan saomi.murai@takeda.com ron.dejong@takeda.com.
Saomi
S
Murai
Discovery Biology, Takeda California, Inc., San Diego, CA, U.S.A.
Jennifer
J
Matuszkiewicz
Pharmacology Research Laboratory II, Pharmaceutical Research Laboratories, Takeda Pharmaceutical Company Ltd., Kanagawa, Japan.
Yuumi
Y
Okuzono
Pharmacology Research Laboratory II, Pharmaceutical Research Laboratories, Takeda Pharmaceutical Company Ltd., Kanagawa, Japan.
Hiroyuki
H
Miya
Discovery Biology, Takeda California, Inc., San Diego, CA, U.S.A. saomi.murai@takeda.com ron.dejong@takeda.com.
Ron
R
DE Jong
D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D002243:Carbolines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology*; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D002243:Carbolines; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D013450:Sulfones; C583854:TAK-901; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C576921:AURKB protein, human; D064107:Aurora Kinase B
Aurora B kinase inhibitor; BCL-xL; TAK-901; synthetic lethal screen