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Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients

Departments of ¹ Pathology and Laboratory Medicine, ² Human Genetics, and ³ Neurology and ⁴ Henry E. Singleton Brain Tumor Program, University of California-Los Angeles David Geffen School of Medicine; Departments of ⁵ Molecular and Medical Pharmacology and ⁶ Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, California; ⁷ Brain Tumor Research Center, Department of Neurological Surgery, University of California-San Francisco, San Francisco, California; ⁸ Ludwig Institute for Cancer Research, Melbourne Branch, Austin Hospital, Melbourne, Victoria, Australia; ⁹ Neuroscience Graduate Program, Mayo Clinic, Rochester, Minnesota; ¹⁰ Genomics Institute of the Novartis Research Foundation, San Diego, California; ¹¹ Department of Radiation Oncology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts; ¹² Pharmaceutical Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey; ¹³ Ludwig Institute for Cancer Research, University of California-San Diego, La Jolla, California; and ¹⁴ Monash Institute of Medical Research, Clayton, Victoria, Australia

Requests for reprints: Paul S. Mischel, 10833 Le Conte Avenue, Box 951732, Los Angeles, CA 90095. Phone: 310-794-5223; Fax: 310-206-8290; E-mail: pmischel{at}mednet.ucla.edu.

Key Words: Fyn • Src • EGFR • glioblastoma • targeted therapy

Activating epidermal growth factor receptor (EGFR) mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors are infrequent and short-lived. We show that the Src family kinases (SFK) Fyn and Src are effectors of oncogenic EGFR signaling, enhancing invasion and tumor cell survival in vivo. Expression of a constitutively active EGFR mutant, EGFRvIII, resulted in activating phosphorylation and physical association with Src and Fyn, promoting tumor growth and motility. Gene silencing of Fyn and Src limited EGFR- and EGFRvIII-dependent tumor cell motility. The SFK inhibitor dasatinib inhibited invasion, promoted tumor regression, and induced apoptosis in vivo, significantly prolonging survival of an orthotopic glioblastoma model expressing endogenous EGFRvIII. Dasatinib enhanced the efficacy of an anti-EGFR monoclonal antibody (mAb 806) in vivo, further limiting tumor growth and extending survival. Examination of a large cohort of clinical samples showed frequent coactivation of EGFR and SFKs in glioblastoma patients. These results establish a mechanism linking EGFR signaling with Fyn and Src activation to promote tumor progression and invasion in vivo and provide rationale for combined anti-EGFR and anti-SFK targeted therapies. [Cancer Res 2009;69(17):6889–98]