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The extent of decelerated or blocked cell proliferation after antibody treatment that is targeted to EGFR and to Her2 depends both on EGFR and Her2 co-expression and on antibody combination used in the treatment setting. Cetuximab did not enhance any inhibitory effect of Trastuzumab or Pertuzumab, most probably due to the dominant overexpression of Her2. Cell susceptibility to Trastuzumab/Pertuzumab, both targeted to Her2, was defined by the ratio of EGFR/Her2 co-expression.

Clear cell sarcoma of soft tissue (CCSST) represents a highly malignant tumor of the musculoskeletal system that is characterized by the chromosomal translocation t(12;22)(q13;q12) of the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1). In a former microarray expression study, we identified ERBB3, a member of the epidermal growth factor receptor (EGFR) family, as a promising new diagnostic marker in the differential diagnosis of CCSST. Here we show that, besides ErbB3, all CCSST cell lines (n = 8) also express the ErbB2 receptor or the ErbB4 receptor, representing an adequate coreceptor of ErbB3. The phosphorylation status of ErbB3 revealed these receptor pairs to be either constitutively activated in CCSST cells with high neuregulin-1 (NRG1) expression (n = 4) or activatable by exogenic NRG1 in cells showing low amounts of NRG1 mRNA (n = 4). Exogenous NRG1 stimulated the growth of a subset of CCSST cells but did not affect the kinetics of another subset. This difference was not strictly dependent on endogenous NRG1 expression; however, the growth-inhibiting effect of the pan-ErbB tyrosine kinase inhibitor CI-1033 or PD158780 clearly correlated with NRG1 expression indicating an autocrine growth stimulation loop which may constitute an interesting target of new therapeutic strategies in this tumor entity.

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Abstract. The epidermal growth factor receptor (EGFR, ErbB1) is frequently dysregulated in a variety of solid human tumors, including malignant glioma. EGFR expression has been associated with disease progression, resistance to standard therapies and poor survival. The application of small interfering RNAs (siRNAs) has become an effective and highly specific tool to modulate gene expression, and a wide range of oncogenes have been silenced successfully. Here we show the siRNA-mediated down-regulation of EGFR in two established glioma cell lines with different EGFR expression levels (U373 MG, LN18). The expression of EGFR mRNA and protein was down-regulated by 70-90%. However, siRNA treatment had no inhibitory effect on cell proliferation, migration and activation status of EGFR-coupled signaling cascades. In accordance with these results, gene expression analysis with microarrays revealed only small, albeit specific changes in expression patterns. In conclusion, these data indicate that the specific down-regulation of EGFR might not be sufficient for a single agent therapeutic approach in malignant glioma. IntroductionMalignant glioma represent the most common primary brain tumors in the adult. Their anatomical localization, the infiltration of the surrounding normal brain parenchyma and the suppression of a tumor-directed immune response contribute to their highly aggressive phenotype. Despite extensive efforts to improve surgery, radiotherapy and chemotherapy, the median survival for patients with glioblastoma multiforme (GBM) averages only 14 months (1). One of the most frequently altered genes in glioblastoma is the epidermal growth factor receptor (EGFR, ErbB1, HER-1). EGFR gene amplification occurs in 40-50% of GBM, and tumors without amplification might also display an overexpression of this receptor (2-4). A common mutation (EGFRvIII), occurring in about half of the glioma with receptor amplification, confers enhanced tumorigenicity by rendering the receptor constitutively active (5). EGFR represents the prototype of class I receptor tyrosine kinases (RTKs). Besides EGFR, the ErbB family of receptors comprises three more members, ErbB2 (HER-2/NEU), ErbB3 (HER-3) and ErbB4 (HER-4). Receptor activation takes place after binding of specific ligands, e.g., epidermal growth factor (EGF), transforming growth factor · (TGF·), Amphiregulin, heparin-binding EGF (6). Ligand binding induces receptor homo-or heterodimerization and activation of the tyrosine kinase domain, which in turn phosphorylates both the receptor itself and downstream effector molecules. This results in signaling through multiple pathways, including the activation of extracellular regulated kinases 1/2 (ERK1/2), protein kinase B (PKB) and members of the signal transducer and activator of transcription (STAT) family. Ultimately, cells respond with enhanced proliferation, migration and transcriptional activity, as well as decreased apoptosis (7-9). Several new strategies have been developed to target EGFR, including monoclonal antibodies (mAbs) (...