Fyn and Src are effectors of oncogenic epidermal growth factor receptor signaling in glioblastoma patients

Kan V. Lu, Shaojun Zhu, Anna Cvrljevic, Tiffany T. Huang, Shawn Sarkaria, David Ahkavan, Julie Dang, Eduard B. Dinca, Seema B. Plaisier, Isaac Oderberg, Yohan Lee, Zugen Chen, Jeremy S. Caldwell, Yongmin Xie, Joseph A. Loo, David Seligson, Arnab Chakravari, Francis Y. Lee, Roberto Weinmann, Timothy F. CloughesyStanley F. Nelson, Gabriele Bergers, Thomas Graeber, Frank B. Furnari, C. David James, Webster K. Cavenee, Terrance G. Johns, Paul S. Mischel

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

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, promoti ng 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.

Original languageEnglish (US)
Pages (from-to)6889-6898
Number of pages10
JournalCancer Research
Volume69
Issue number17
DOIs
StatePublished - Sep 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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