The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors

被引：455

作者：

Hedvat, Michael ^{[1
]}

Huszar, Dennis ^{[2
]}

Herrmann, Andreas ^{[1
]}

Gozgit, Joseph M. ^{[2
]}

Schroeder, Anne ^{[1
]}

Sheehy, Adam ^{[2
]}

Buettner, Ralf ^{[1
]}

Proia, David ^{[2
]}

Kowolik, Claudia M. ^{[1
]}

Xin, Hong ^{[1
]}

Armstrong, Brian ^{[1
]}

Bebernitz, Geraldine ^{[2
]}

Weng, Shaobu ^{[2
]}

Wang, Lin ^{[2
]}

Ye, Minwei ^{[2
]}

McEachern, Kristen ^{[2
]}

Chen, Huawei ^{[2
]}

Morosini, Deborah ^{[2
]}

Bell, Kirsten ^{[2
]}

Alimzhanov, Marat ^{[2
]}

Ioannidis, Stephanos ^{[2
]}

McCoon, Patricia ^{[2
]}

Cao, Zhu A. ^{[2
]}

Yu, Hua ^{[1
]}

Jove, Richard ^{[1
]}

Zinda, Michael ^{[2
]}

机构：

[1] City Hope Canc Ctr, Irell & Manella Grad Sch Biol Sci, Beckman Res Inst, Duarte, CA 91010 USA

[2] AstraZeneca R&D Boston, Canc Biosci, Waltham, MA 02451 USA

来源：

CANCER CELL | 2009年 / 16卷 / 06期

基金：

美国国家卫生研究院;

关键词：

CANCER CELL-GROWTH; CONSTITUTIVE ACTIVATION; CARCINOMA CELLS; AUTOCRINE IL-6; KINASE; PATHWAY; SRC; INTERLEUKIN-6; TRANSDUCER; EXPRESSION;

D O I：

10.1016/j.ccr.2009.10.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：487 / 497

页数：11

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