Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization
Authors:
- 28 June 2010
- journal article
- research article
- Published by National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 107 (28) , 12634-12639
Abstract
Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This “addiction” can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility.Keywords
This publication has 22 references indexed in Scilit:
- Inhibition of Aurora B kinase sensitizes a subset of human glioma cells to TRAIL concomitant with induction of TRAIL-R2Cell Death & Differentiation, 2008
- The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralizedCancer Cell, 2006
- The Aurora Kinase Inhibitor VX-680 Induces Endoreduplication and Apoptosis Preferentially in Cells with Compromised p53-Dependent Postmitotic Checkpoint FunctionCancer Research, 2006
- Differential Targeting of Prosurvival Bcl-2 Proteins by Their BH3-Only Ligands Allows Complementary Apoptotic FunctionMolecular Cell, 2005
- VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivoNature Medicine, 2004
- BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and BakGenes & Development, 2001
- Eradication of human non-Hodgkin's lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with low-dose cyclophosphamide.2000
- Expression of Bcl-xL and loss of p53 can cooperate to overcome a cell cycle checkpoint induced by mitotic spindle damage.Genes & Development, 1996
- A bcl-2/IgH antisense transcript deregulates bcl-2 gene expression in human follicular lymphoma t(14;18) cell lines.1996
- Criteria for Analyzing Interactions between Biologically Active Agents1981