JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer

Cancer Cell. 2012 Dec 11;22(6):796-811. doi: 10.1016/j.ccr.2012.10.023.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Female
  • Humans
  • Insulin Receptor Substrate Proteins / metabolism
  • Interleukin-8 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis / drug therapy*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Receptors, Interleukin-8A / metabolism
  • STAT5 Transcription Factor / antagonists & inhibitors*
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Insulin Receptor Substrate Proteins
  • Interleukin-8
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Interleukin-8A
  • STAT5 Transcription Factor
  • TOR Serine-Threonine Kinases
  • Janus Kinase 2