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Updated: Jun 11, 2026

Examining BCL-2 Family Function with Large Unilamellar Vesicles
Published on: October 5, 2012
Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization
O Jameel Shah1, Xiaoyu Lin, Leiming Li
1Oncology Division and Advanced Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6121, USA.
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.
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