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The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors
Michael Hedvat ,
Dennis Huszar ,
Andreas Herrmann ,
Joseph M. Gozgit ,
Anne Schroeder ,
Adam Sheehy ,
Ralf Buettner ,
David Proia ,
Claudia M. Kowolik ,
Hong Xin ,
Brian Armstrong ,
Geraldine Bebernitz ,
Shaobu Weng ,
Lin Wang ,
Minwei Ye ,
Kristen McEachern ,
Huawei Chen ,
Deborah Morosini ,
Kirsten Bell ,
Marat Alimzhanov ,
Stephanos Ioannidis ,
Patricia McCoon ,
Zhu A. Cao ,
Hua Yu ,
Richard Jove ,
Michael Zinda
December 2009
December 2009
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Abstract
Persistent activation of Stat3 is oncogenic and is prevalent in a wide variety of
human cancers. Chronic cytokine stimulation is associated with Stat3 activation in
some tumors, implicating cytokine receptor-associated Jak family kinases. Using Jak2
inhibitors, we demonstrate a central role of Jaks in modulating basal and cytokine-induced
Stat3 activation in human solid tumor cell lines. Inhibition of Jak2 activity is associated
with abrogation of Stat3 nuclear translocation and tumorigenesis. The Jak2 inhibitor
AZD1480 suppresses the growth of human solid tumor xenografts harboring persistent
Stat3 activity. We demonstrate the essential role of Stat3 downstream of Jaks by inhibition
of tumor growth using short hairpin RNA targeting Stat3. Our data support a key role
of Jak kinase activity in Stat3-dependent tumorigenesis.