Abstract
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Cell Death / drug effects
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Cell Line, Tumor
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Female
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Humans
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Insulin Receptor Substrate Proteins / metabolism
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Interleukin-8 / metabolism
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Metastasis / drug therapy*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Receptors, Interleukin-8A / metabolism
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STAT5 Transcription Factor / antagonists & inhibitors*
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STAT5 Transcription Factor / metabolism
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
Substances
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Insulin Receptor Substrate Proteins
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Interleukin-8
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Interleukin-8A
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STAT5 Transcription Factor
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Janus Kinase 2
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TOR Serine-Threonine Kinases