Open AccessBcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization
Author(s) -
O. Jameel Shah,
Xiaoyu Lin,
Leiming Li,
Xiaoli Huang,
Junling Li,
Mark G. Anderson,
Hua Tang,
Luis E. Rodrı́guez,
Scott E. Warder,
Shaun M. McLoughlin,
Jun Chen,
Joann P. Palma,
Keith B. Glaser,
Cherrie K. Donawho,
Stephen W. Fesik,
Yu Shen
Publication year - 2010
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0913615107
Subject(s) - druggability , aurora kinase , aurora inhibitor , aurora b kinase , cancer research , kinase , biology , viability assay , synthetic lethality , apoptosis , cell , microbiology and biotechnology , cell cycle , genetics , cell division , spindle apparatus , gene , dna repair
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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