Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization.
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.
Shah
O Jameel
OJ
Oncology Division and Advanced Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6121, USA.
Lin
Xiaoyu
X
Li
Leiming
L
Huang
Xiaoli
X
Li
Junling
J
Anderson
Mark G
MG
Tang
Hua
H
Rodriguez
Luis E
LE
Warder
Scott E
SE
McLoughlin
Shaun
S
Chen
Jun
J
Palma
Joann
J
Glaser
Keith B
KB
Donawho
Cherrie K
CK
Fesik
Stephen W
SW
Shen
Yu
Y
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
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