title: Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization.
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.
authors.affiliation: Oncology Division and Advanced Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6121, USA.
authors.forename: O Jameel
authors.initials: OJ
authors.lastname: Shah
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lin
authors.forename: Leiming
authors.initials: L
authors.lastname: Li
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.forename: Junling
authors.initials: J
authors.lastname: Li
authors.forename: Mark G
authors.initials: MG
authors.lastname: Anderson
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.forename: Luis E
authors.initials: LE
authors.lastname: Rodriguez
authors.forename: Scott E
authors.initials: SE
authors.lastname: Warder
authors.forename: Shaun
authors.initials: S
authors.lastname: McLoughlin
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Joann
authors.initials: J
authors.lastname: Palma
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
authors.forename: Cherrie K
authors.initials: CK
authors.lastname: Donawho
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000814:Aniline Compounds; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064107:Aurora Kinase B; D064127:Aurora Kinases; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D013449:Sulfonamides
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013449:Sulfonamides; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C528561:navitoclax