ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice

Al Charest*, Erik W. Wilker, Margaret E. McLaughlin, Keara Michelle Lane, Ram Gowda, Shanie Coven, Kevin McMahon, Steven Kovach, Yun Feng, Michael B. Yaffe, Tyler Jacks, David Housman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domain-containing phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)7473-7481
Number of pages9
JournalCancer Research
Volume66
Issue number15
DOIs
StatePublished - Aug 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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