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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 15; pp. 7473 - 7481
• Main Authors: CHAREST, Al, WILKER, Erik W, JACKS, Tyler, HOUSMAN, David, MCLAUGHLIN, Margaret E, LANE, Keara, GOWDA, Ram, COVEN, Shanie, MCMAHON, Kevin, KOVACH, Steven, YUN FENG, YAFFE, Michael B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2006
• Subjects: Animals; Astrocytoma - enzymology; Astrocytoma - metabolism; Astrocytoma - pathology; Biological and medical sciences; Brain Neoplasms - enzymology; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cyclin-Dependent Kinase Inhibitor p16 - deficiency; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Enzyme Activation; Glioblastoma - enzymology; Glioblastoma - metabolism; Glioblastoma - pathology; Intracellular Signaling Peptides and Proteins - metabolism; Medical sciences; Mice; Neurology; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinases - metabolism; Protein Phosphatase 2; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases - metabolism; Protein-Tyrosine Kinases - biosynthesis; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; SH2 Domain-Containing Protein Tyrosine Phosphatases; Signal Transduction; src Homology Domains; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p14ARF - deficiency; Tumor Suppressor Protein p14ARF - genetics; Tumors of the nervous system. Phacomatoses; Protein kinase mTOR; Nervous system diseases; Enzyme; Transferases; Rodentia; Glioblastoma; Phosphoric monoester hydrolases; Src Homology 2 domain; Esterases; Malignant tumor; 1-Phosphatidylinositol 3-kinase; Malignant glioma; Signal transduction; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Hydrolases; Phosphatidylinositol-3-phosphatase; Fusion protein; Protein-tyrosine kinase
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-06-1193

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.