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

Department of Pathology and Laboratory Medicine, University of California-Los Angeles David Geffen School of Medicine, USA.
Cancer Research (Impact Factor: 9.33). 09/2009; 69(17):6889-98. DOI: 10.1158/0008-5472.CAN-09-0347
Source: PubMed


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.

Download full-text


Available from: Stanley F Nelson, Jul 30, 2014
1 Follower
16 Reads
    • "Stettner et al. analyzed GBM tumors at autopsy and showed that Lyn activity levels were significantly elevated compared to Src and Fyn activity , accounting for >90% of the SFK activity in the GBM samples , vs. 30% of the SFK activity in various non-GBM brain samples (Stettner et al., 2005). On the other hand, Lu et al. has demonstrated the importance of Fyn and Src to EGFR and EGFRvIII signaling in both cell culture and orthotopic xenograft contexts (Lu et al., 2009). Finally, Han et al. have shown that Src and Yes, but not Fyn, Lyn, or Lck, are important to glioma stem cell migration on laminin in culture (Han et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Src-family kinase (SFK) signaling impacts multiple tumor-related properties, particularly in the context of the brain tumor glioblastoma. Consequently, the pan-SFK inhibitor dasatinib has emerged as a therapeutic strategy, despite physiologic limitations to its effectiveness in the brain. We investigated the importance of individual SFKs (Src, Fyn, Yes, and Lyn) to glioma tumor biology by knocking down individual SFK expression both in culture (LN229, SF767, GBM8) and orthotopic xenograft (GBM8) contexts. We evaluated the effects of these knockdowns on tumor cell proliferation, migration, and motility-related signaling in culture, as well as overall survival in the orthotopic xenograft model. The four SFKs differed significantly in their importance to these properties. In culture, Src, Fyn, and Yes knockdown generally reduced growth and migration and altered motility-related phosphorylation patterns while Lyn knockdown did so to a lesser extent. However the details of these effects varied significantly depending on the cell line: in no case were conclusions about the role of a particular SFK applicable to all of the measures or all of the cell types examined. In the orthotopic xenograft model, mice implanted with non-target or Src or Fyn knockdown cells showed no differences in survival. In contrast, mice implanted with Yes knockdown cells had longer survival, associated with reduced tumor cell proliferation. Those implanted with Lyn knockdown cells had shorter survival, associated with higher overall tumor burden. Together, our results suggest that Yes signaling directly affects tumor cell biology in a pro-tumorigenic manner, while Lyn signaling affects interactions between tumor cells and the microenvironment in an anti-tumor manner. In the context of therapeutic targeting of SFKs, these results suggest that pan-SFK inhibitors may not produce the intended therapeutic benefit when Lyn is present. Copyright © 2015. Published by Elsevier B.V.
    Molecular oncology 06/2015; 16(suppl 5). DOI:10.1016/j.molonc.2015.06.001 · 5.33 Impact Factor
  • Source
    • "Approximately 40% of GBMs shows EGFR gene amplification and overexpression [18,19].Amplification of the EGFR gene is often associated with a mutation that encodes for a truncated form of the receptor, known as EGFR variant vIII (EGFRvIII), lacking the extracellular binding domain and leading to constitutive activation of tyrosine kinases [20, 21]. Expression of EGFRvIII correlates with poor survival in GBM patients [22] and promotes glioma cell migration [23], tumor growth, invasion, survival [24] and angiogenesis [25]. Furhtermore, EGFRvIII causes enhanced apoptosis resistance. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Malignant brain tumours are one of the most relevant causes of morbidity and mortality across a wide range of individuals. Malignant glioma is the most common intra axial tumor in the adult. Many researches on this theme brought advances in the knowledge of gliomas biology and pathogenesis and to the development of new agents for targeted molecular therapy. Recent studies focused on either tumor metabolism analysis or epigenetic regulation in the pathogenesis or maintenance of brain tumors. This Review summarizes these developments analyzing molecular pathology and possible further developments for targeted therapies.
    09/2014; 10:29-37.
  • Source
    • "o - oncogenic processes such as cell viability , migration , invasion , and metastasis ( Boukerche et al . , 2010 ; Boukerche , Su , Prvot , Sarkar , & Fisher , 2008 ; Du et al . , 2009 ) . These proteins are often activated in GBM tumors and cell lines ( Du et al . , 2009 ; Stettner et al . , 2005 ) and are effectors of oncogenic EGFR signaling ( Lu et al . , 2009 ) . In 31 samples of GBM tumors , SRC was significantly activated in 61% . Inhibition via dasatinib inhibits viability and migration in vitro as well as tumor growth in vivo ( Du et al . , 2009 ) . Src family kinases are among the most frequently observed tyrosine kinase activations in a study of 130 human cancer cells , along with EGFR"
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite an increased emphasis on developing new therapies for malignant gliomas, they remain among the most intractable tumors faced today as they demonstrate a remarkable ability to evade current treatment strategies. Numerous candidate treatments fail at late stages, often after showing promising preclinical results. This disconnect highlights the continued need for improved animal models of glioma, which can be used to both screen potential targets and authentically recapitulate the human condition. This review examines recent developments in the animal modeling of glioma, from more established rat models to intriguing new systems using Drosophila and zebrafish that set the stage for higher throughput studies of potentially useful targets. It also addresses the versatility of mouse modeling using newly developed techniques recreating human protocols and sophisticated genetically engineered approaches that aim to characterize the biology of gliomagenesis. The use of these and future models will elucidate both new targets and effective combination therapies that will impact on disease management.
    Advances in Cancer Research 06/2014; 121:261-330. DOI:10.1016/B978-0-12-800249-0.00007-X · 5.32 Impact Factor
Show more