Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII

Pedersen, Mikkel Wandahl; Pedersen, Nina Marie; Ottesen, Lone H.; Poulsen, Hans Skovgaard

doi:10.1038/sj.bjc.6602793

Cited by 71 publications

(37 citation statements)

References 22 publications

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“…Protein levels were determined by preparing whole-cell lysates from cell lines and xenografts and analyzed by immunoblot as described previously (16).…”

Section: Methodsmentioning

confidence: 99%

Sym004: A Novel Synergistic Anti–Epidermal Growth Factor Receptor Antibody Mixture with Superior Anticancer Efficacy

et al. 2010

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Epidermal growth factor receptor (EGFR) is a validated therapeutic target in cancer and EGFR antagonists with greater effectiveness than existing clinical agents remain of interest. Here, we report a novel approach based on Sym004, a mixture of two anti-EGFR monoclonal antibodies directed against distinct nonoverlapping epitopes in EGFR extracellular domain III. Like anti-EGFR monoclonal antibodies in current clinical use, Sym004 inhibits cancer cell growth and survival by blocking ligand-binding receptor activation and phosphorylation and downstream receptor signaling. However, unlike the other antibodies, Sym004 induces rapid and efficient removal of the receptor from the cancer cell surface by triggering EGFR internalization and degradation. Compared with reference anti-EGFR monoclonal antibodies, Sym004 exhibited more pronounced growth inhibition in vitro and superior efficacy in vivo. Together, these findings illustrate a strategy to target EGFR more effectively than existing clinical antibodies.

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“…Protein levels were determined by preparing whole-cell lysates from cell lines and xenografts and analyzed by immunoblot as described previously (16).…”

Section: Methodsmentioning

confidence: 99%

Sym004: A Novel Synergistic Anti–Epidermal Growth Factor Receptor Antibody Mixture with Superior Anticancer Efficacy

et al. 2010

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“…Epidermal growth factor receptor (EGFR) is frequently amplified and/or mutated in a number of human tumors, and abnormal signaling from this receptor is believed to contribute to the malignant phenotype observed in these tumors (17). This has inspired the development of specific pharmacological inhibitors of the EGFR tyrosine kinase such as gefitinib, which disrupts EGFR kinase activity by reversibly binding within the ATP-binding pocket of the EGFR protein (18).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of EGFR pathway-related genes in the circulation is highly correlated with EGFR mutations and overexpression in paired cancer tissue from patients with non-small cell lung cancer

Chen

Chiu²,

Yen³

et al. 2010

Oncol Rep

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Abstract. Epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) have been established as a treatment option in patients with advanced non-small cell lung cancer (NSCLC). Clinically, PCR and RFLP are commonly used to evaluate the efficacy of TKIs, and these methods require cancer tissues to proceed. In the event a peripheral blood test is able to replace current evaluation methods, a greater clinical application advantage may be achieved. Therefore, in this study, we selected 30 EGFR pathway-related genes and constructed activated EGFR chips to identify overexpression of EGFR pathway-related genes from the peripheral blood of 72 NSCLC patients and 100 normal subjects. According to ROC curve analysis, the best chip interpretation cutoff value was 11 genes. Correlation analysis showed high significance among EGFR mutations, overexpression and the overexpression of EGFR pathway-related genes (p<0.0001). The potential application of this new technique may provide an accurate, instantaneous and convenient drug evaluation tool.

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“…Because of the absence of this mutant receptor in normal tissue, EGFRvIII is an attractive therapeutic target. Although EGFR inhibitors, such as erlotinib and gefitinib, inhibit EGFR, EGFRvIII bearing xenograft models and cell lines are resistant to these inhibitors (15,16). Therapeutic agents directly targeting EGFRvIII in murine GBM xenografts initially resulted in reduced tumor volume and a modest increase in survival (17).…”

Section: Glioblastoma Multiforme (Gbm)mentioning

confidence: 99%

Molecular Characterization of EGFR and EGFRvIII Signaling Networks in Human Glioblastoma Tumor Xenografts

Johnson

Rosario

Bryson

et al. 2012

Molecular & Cellular Proteomics

107

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Glioblastoma multiforme (GBM) is a malignant primary brain tumor with a mean survival of 15 months with the current standard of care. Genetic profiling efforts have identified the amplification, overexpression, and mutation of the wild-type (wt) epidermal growth factor receptor tyrosine kinase (EGFR) in ϳ50% of GBM patients. The genetic aberration of wtEGFR is frequently accompanied by the overexpression of a mutant EGFR known as EGFR variant III (EGFRvIII, de2-7EGFR, ⌬EGFR), which is expressed in 30% of GBM tumors. The molecular mechanisms of tumorigenesis driven by EGFRvIII overexpression in human tumors have not been fully elucidated. To identify specific therapeutic targets for EGFRvIII driven tumors, it is important to gather a broad understanding of EGFRvIII specific signaling. Here, we have characterized signaling through the quantitative analysis of protein expression and tyrosine phosphorylation across a panel of glioblastoma tumor xenografts established from patient surgical specimens expressing wtEGFR or overexpressing wtEGFR (wtEGFR؉) or EGFRvIII (EGFRvIII؉). S100A10 (p11), major vault protein, guanylate-binding protein 1(GBP1), and carbonic anhydrase III (CAIII) were identified to have significantly increased expression in EGFRvIII expressing xenograft tumors relative to wtEGFR xenograft tumors. Increased expression of these four individual proteins was found to be correlated with poor survival in patients with GBM; the combination of these four proteins represents a prognostic signature for poor survival in gliomas. Integration of protein expression and phosphorylation data has uncovered significant heterogeneity among the various tumors and has highlighted several novel pathways, related to EGFR trafficking, activated in glioblastoma. The pathways and proteins identified in these tumor xenografts represent potential therapeutic targets for this disease. Molecular & Cellular Proteomics

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Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII

Cited by 71 publications

References 22 publications

Sym004: A Novel Synergistic Anti–Epidermal Growth Factor Receptor Antibody Mixture with Superior Anticancer Efficacy

Sym004: A Novel Synergistic Anti–Epidermal Growth Factor Receptor Antibody Mixture with Superior Anticancer Efficacy

Overexpression of EGFR pathway-related genes in the circulation is highly correlated with EGFR mutations and overexpression in paired cancer tissue from patients with non-small cell lung cancer

Molecular Characterization of EGFR and EGFRvIII Signaling Networks in Human Glioblastoma Tumor Xenografts

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