Blockade of glioma proliferation through allosteric inhibition of JAK2

Sci Signal. 2013 Jul 9;6(283):ra55. doi: 10.1126/scisignal.2003900.

Abstract

The gene that encodes the epidermal growth factor receptor (EGFR) is frequently overexpressed or mutated in human cancers, including glioblastoma. However, the efficacy of EGFR-targeted small-molecule inhibitors or monoclonal antibodies in glioblastomas that also have mutation or deletion of the gene encoding phosphatase and tensin homolog (PTEN) has been modest. We found that EGFR signaling was blocked by a small molecule (G5-7) that selectively inhibited Janus kinase 2 (JAK2)-mediated phosphorylation and activation of EGFR and STAT3 (signal transducer and activator of transcription 3) by binding to JAK2, thereby decreasing the activity of downstream signaling by mTOR (mammalian target of rapamycin) and inducing cell cycle arrest. G5-7 inhibited the proliferation of PTEN-deficient glioblastoma cell lines harboring a constitutively active variant of EGFR (U87MG/EGFRvIII) and human glioblastoma explant neurosphere cultures, but the drug only weakly inhibited the proliferation of either glioblastoma cell lines that were wild type for EGFR and stably transfected with PTEN (U87MG/PTEN) or normal neural progenitor cells and astrocytes. Additionally, G5-7 reduced vascular endothelial growth factor (VEGF) secretion and endothelial cell migration and induced apoptosis in glioblastoma xenografts, thereby suppressing glioblastoma growth in vivo. Furthermore, G5-7 was more potent than EGFR or JAK2 inhibitors that interfere with either ligand or adenosine 5'-triphosphate (ATP) binding at impeding glioblastoma cell proliferation, demonstrating that this allosteric JAK2 inhibitor may be an effective clinical strategy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / genetics
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gene Deletion
  • Glioma / drug therapy*
  • Glioma / enzymology
  • Glioma / genetics
  • Glioma / pathology
  • Heterografts
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neural Stem Cells / enzymology
  • Neural Stem Cells / pathology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics

Substances

  • Protein Kinase Inhibitors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • EGFR protein, human
  • EGFR protein, mouse
  • ErbB Receptors
  • JAK2 protein, human
  • Jak2 protein, mouse
  • Janus Kinase 2
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse