JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer.
- Britschgi A Friedrich Miescher Institute for Biomedical Research, Basel, CH-4058, Switzerland.
- Andraos R
- Brinkhaus H
- Klebba I
- Romanet V
- Müller U
- Murakami M
- Radimerski T
- Bentires-Alj M
- 2012-12-15
Published in:
- Cancer cell. - 2012
Animals
Breast Neoplasms
Cell Death
Cell Line, Tumor
Female
Humans
Insulin Receptor Substrate Proteins
Interleukin-8
Janus Kinase 2
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, SCID
Neoplasm Metastasis
Phosphatidylinositol 3-Kinases
Phosphoinositide-3 Kinase Inhibitors
Receptors, Interleukin-8A
STAT5 Transcription Factor
Signal Transduction
TOR Serine-Threonine Kinases
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.ccr.2012.10.023
- PMID 23238015
- Persistent URL
- https://sonar.ch/global/documents/298923
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