JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer

被引：202

作者：

Britschgi, Adrian ^{[1
]}

Andraos, Rita ^{[2
]}

Brinkhaus, Heike ^{[1
]}

Klebba, Ina ^{[1
]}

Romanet, Vincent ^{[2
]}

Mueller, Urs ^{[1
]}

Murakami, Masato ^{[2
]}

Radimerski, Thomas ^{[2
]}

Bentires-Alj, Mohamed ^{[1
]}

机构：

[1] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland

[2] Novartis Inst Biomed Res, Dis Area Oncol, CH-4057 Basel, Switzerland

来源：

CANCER CELL | 2012年 / 22卷 / 06期

基金：

欧洲研究理事会;

关键词：

INSULIN-RECEPTOR SUBSTRATE-1; GROWTH-HORMONE; TYROSINE PHOSPHORYLATION; SIGNALING PATHWAY; MET AMPLIFICATION; PI3K PATHWAY; LUNG-CANCER; IN-VIVO; KINASE; CELLS;

D O I：

10.1016/j.ccr.2012.10.023

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Hyperactive PI3K/mTOR signaling is prevalent in human malignancies and its inhibition has potent antitumor consequences. Unfortunately, single-agent targeted cancer therapy is usually short-lived. We have discovered a JAK2/STAT5-evoked positive feedback loop that dampens the efficacy of PI3K/mTOR inhibition. Mechanistically, PI3K/mTOR inhibition increased IRS1-dependent activation of JAK2/STAT5 and secretion of IL-8 in several cell lines and primary breast tumors. Genetic or pharmacological inhibition of JAK2 abrogated this feedback loop and combined PI3K/mTOR and JAK2 inhibition synergistically reduced cancer cell number and tumor growth, decreased tumor seeding and metastasis, and also increased overall survival of the animals. Our results provide a rationale for combined targeting of the PI3K/mTOR and JAK2/STAT5 pathways in triple-negative breast cancer, a particularly aggressive and currently incurable disease.

引用

页码：796 / 811

页数：16

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