Identification of an EGFRvIII-JNK2-HGF/c-Met–Signaling Axis Required for Intercellular Crosstalk and Glioblastoma Multiforme Cell Invasion

• Published in: Molecular pharmacology 2015-12, Vol.88 (6), p.962-969
• Main Authors: Saunders, Vanessa C., Lafitte, Marie, Adrados, Isabel, Quereda, Victor, Feurstein, Daniel, Ling, YuanYuan, Fallahi, Mohammad, Rosenberg, Laura H., Duckett, Derek R.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Glioblastoma - metabolism; Glioblastoma - pathology; Hepatocyte Growth Factor - biosynthesis; Humans; Intercellular Junctions - metabolism; Male; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 9 - biosynthesis; Neoplasm Invasiveness - pathology; Receptor Protein-Tyrosine Kinases - biosynthesis; Receptor, Epidermal Growth Factor - biosynthesis; Signal Transduction - physiology; Xenograft Model Antitumor Assays - methods
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.115.097774

Glioblastoma multiforme (GBM) is the most aggressive and common form of adult brain cancer. Current therapeutic strategies include surgical resection, followed by radiotherapy and chemotherapy. Despite such aggressive multimodal therapy, prognosis remains poor, with a median patient survival of 14 months. A proper understanding of the molecular drivers responsible for GBM progression are therefore necessary to instruct the development of novel targeted agents and enable the design of effective treatment strategies. Activation of the c-Jun N-terminal kinase isoform 2 (JNK2) is reported in primary brain cancers, where it associates with the histologic grade and amplification of the epidermal growth factor receptor (EGFR). In this manuscript, we demonstrate an important role for JNK2 in the tumor promoting an invasive capacity of EGFR variant III, a constitutively active mutant form of the receptor commonly found in GBM. Expression of EGFR variant III induces transactivation of JNK2 in GBM cells, which is required for a tumorigenic phenotype in vivo. Furthermore, JNK2 expression and activity is required to promote increased cellular invasion through stimulation of a hepatocyte growth factor–c-Met signaling circuit, whereby secretion of this extracellular ligand activates the receptor tyrosine kinase in both a cell autonomous and nonautonomous manner. Collectively, these findings demonstrate the cooperative and parallel activation of multiple RTKs in GBM and suggest that the development of selective JNK2 inhibitors could be therapeutically beneficial either as single agents or in combination with inhibitors of EGFR and/or c-Met.