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Molecular Pharmacology

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Research ArticleArticle

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

Vanessa C. Saunders, Marie Lafitte, Isabel Adrados, Victor Quereda, Daniel Feurstein, YuanYuan Ling, Mohammad Fallahi, Laura H. Rosenberg and Derek R. Duckett
Molecular Pharmacology December 2015, 88 (6) 962-969; DOI: https://doi.org/10.1124/mol.115.097774
Vanessa C. Saunders
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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Marie Lafitte
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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Isabel Adrados
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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Victor Quereda
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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Daniel Feurstein
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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YuanYuan Ling
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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Mohammad Fallahi
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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Laura H. Rosenberg
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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Derek R. Duckett
Department of Molecular Therapeutics (V.C.S., M.L., I.A., V.Q., D.F., Y.L., D.R.D.), Informatics Core, Scripps Research Institute, Jupiter, Florida (M.F.) and Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, United Kingdom (L.H.R.)
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Abstract

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.

Footnotes

    • Received January 7, 2015.
    • Accepted September 30, 2015.
  • ↵1 V.C.S. and M.L. contributed equally to this work.

  • This work is supported by The Rendina Family Foundation, 2011–2013 Florida Center for Brain Tumor Research (FCBTR)/Accelerate Brain Cancer Cure (ABC2) Grant, and funds from the State of Florida to Scripps Florida. The authors declare no competing financial interests.

  • dx.doi.org/10.1124/mol.115.097774.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (6)
Molecular Pharmacology
Vol. 88, Issue 6
1 Dec 2015
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Research ArticleArticle

JNK2 Mediates EGFRvIII-Driven HGF Production

Vanessa C. Saunders, Marie Lafitte, Isabel Adrados, Victor Quereda, Daniel Feurstein, YuanYuan Ling, Mohammad Fallahi, Laura H. Rosenberg and Derek R. Duckett
Molecular Pharmacology December 1, 2015, 88 (6) 962-969; DOI: https://doi.org/10.1124/mol.115.097774

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Research ArticleArticle

JNK2 Mediates EGFRvIII-Driven HGF Production

Vanessa C. Saunders, Marie Lafitte, Isabel Adrados, Victor Quereda, Daniel Feurstein, YuanYuan Ling, Mohammad Fallahi, Laura H. Rosenberg and Derek R. Duckett
Molecular Pharmacology December 1, 2015, 88 (6) 962-969; DOI: https://doi.org/10.1124/mol.115.097774
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