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EGFR Inhibition (egfr + inhibition)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Immunohistochemical study of epidermal growth factor receptor in adenoid cystic carcinoma of salivary gland origin

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 7 2002
Marilena Vered DMD
Abstract Background Epidermal growth factor (EGF) and its receptor (EGFR) are involved in the development of salivary gland tumors. Recently, treatment modalities for EGFR inhibition have shown an enhanced clinical response in carcinomas of different locations. Adenoid cystic carcinoma (ACC) of salivary gland origin is a malignant tumor with a poor long-term outcome. If salivary gland ACC does exhibit EGFR, then immunotherapy could have a major impact on improving its prognosis. Methods The study consisted of 34 samples of formalin-fixed, paraffin-embedded specimens of salivary gland ACC. Specimens were stained with a mouse antihuman monoclonal antibody for immunohistochemical detection of EGFR. Overlying oral mucosa and adjacent normal salivary ducts served as internal controls. Both membrane and cytoplasmic staining were evaluated. Staining score was calculated by multiplying the percentage of positively stained tumor cells by the intensity of the staining. The highest score for a given tumor was equal to 2. Results In the final analysis, 27 of the 34 specimens were included; 7 were excluded, because the internal control did not reveal any staining. Of these 27 specimens, 23 (85%) stained positively for EGFR with a staining score of 0.05 to 1.8. Three palatal tumors attained the highest scores (one tumor, 1.2, and the remaining two, 1.8). Conclusions Most salivary gland ACC stained positively for EGFR, and in some the staining was quite intense. On the basis of the already proven antitumoral effect of agents acting as EGFR inhibitors, it is suggested that patients with ACC might benefit from these agents, especially when surgery has failed or in those with recurrent or metastatic disease. © 2002 Wiley Periodicals, Inc. Head Neck 24: 632,636, 2002 [source]

Role of Network Branching in Eliciting Differential Short-Term Signaling Responses in the Hypersensitive Epidermal Growth Factor Receptor Mutants Implicated in Lung Cancer

BIOTECHNOLOGY PROGRESS, Issue 3 2008
Jeremy Purvis
We study the effects of EGFR inhibition in wild-type and mutant cell lines upon tyrosine kinase inhibitor TKI treatment through a systems level deterministic and spatially homogeneous model to help characterize the hypersensitive response of the cancer cell lines harboring constitutively active mutant kinases to inhibitor treatment. By introducing a molecularly resolved branched network systems model (the molecular resolution is introduced for EGFR reactions and interactions in order to distinguish differences in activation between wild-type and mutants), we are able to quantify differences in (1) short-term signaling in downstream ERK and Akt activation, (2) the changes in the cellular inhibition EC50 associated with receptor phosphorylation (i.e., 50% inhibition of receptor phosphorylation in the cellular context), and (3) EC50 for the inhibition of activated downstream markers ERK-(p) and Akt-(p), where (p) denotes phosphorylated, upon treatment with the inhibitors in cell lines carrying both wild-type and mutant forms of the receptor. Using the branched signaling model, we illustrate a possible mechanism for preferential Akt activation in the cell lines harboring the oncogenic mutants of EGFR implicated in non-small-cell lung cancer and the enhanced efficacy of the inhibitor erlotinib especially in ablating the cellular Akt-(p) response. Using a simple phenomenological model to describe the effect of Akt activation on cellular decisions, we discuss how this preferential Akt activation is conducive to cellular oncogene addiction and how its disruption can lead to dramatic apoptotic response and hence remarkable inhibitor efficacies. We also identify key network nodes of our branched signaling model through sensitivity analysis as those rendering the network hypersensitive to enhanced ERK-(p) and Akt-(p); intriguingly, the identified nodes have a strong correlation with species implicated in oncogenic transformations in human cancers as well as in drug resistance mechanisms identified for the inhibitors in non-small-cell lung cancer therapy. [source]

CD95-mediated Apoptosis of Human Glioma Cells: Modulation by Epidermal Growth Factor Receptor Activity

BRAIN PATHOLOGY, Issue 1 2002
Joachim P. Steinbach
The death ligands CD95L and Apo2L/TRAIL are promising investigational agents for the treatment of malignant glioma. EGFR is overexpressed in a significant proportion of malignant gliomas in vivo. Here, we report that CD95L-induced cell death is enhanced by EGFR inhibition using tyrphostine AG1478 in 7 of 12 human malignant glioma cell lines. Conversely, CD95-mediated and Apo2L-induced cell death are both inhibited by overexpression of EGFR in LN-229 cells. CD95L-induced cell death augmented by AG1478 is accompanied by enhanced processing of caspase 8. LN-229 cells overexpressing the viral caspase inhibitor, crm-A, are not sensitized to CD95L-induced cell death by AG1478, indicating that EGFR exerts its antiapoptotic properties through a caspase 8-dependent pathway. These data define a modulatory effect of EGFR-activity on death ligand-induced apoptosis and indicate that EGFR inhibition is likely to improve the efficacy of death ligand-based cancer therapies. Furthermore, it is tempting to speculate that EGFR amplification protects tumor cells from death ligand-mediated host immune responses in vivo and that EGFR's effects on death receptor-mediated apoptosis may explain the anti-tumor effects of non-cytotoxic, unarmed anti-EGFR family antibodies. [source]

Signaling of ERBB receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivo

CANCER, Issue 13 2010
Kristen N. Richards MS
Abstract BACKGROUND: ERBB receptor tyrosine kinases can mediate proliferation, migration, adhesion, differentiation, and survival in many types of cells and play critical roles in many malignancies. Recent reports suggest a role for EGFR signaling in proliferation and survival of neuroblastoma, a common form of pediatric cancer that often has an extremely poor outcome. METHODS: The authors examined ERBB family expression in neuroblastoma cell lines and patient samples by flow cytometry, western blot, and quantitative real time polymerase chain reaction (Q-PCR). Response to ERBB inhibition was assessed in vitro by cell-cycle analysis and western blot and in vivo by serial tumor-size measurements. RESULTS: A panel of neuroblastoma cell lines and primary patient tumors expressed EGFR, HER-3, and HER-4, with HER-2 in some tumors. HER-4 mRNA was expressed predominantly in cleavable isoforms. Whereas EGFR inhibition with erlotinib and pan-ERBB inhibition with CI-1033 inhibited EGF-induced phosphorylation of EGFR, AKT, and ERK1/2, only CI-1033 induced growth inhibition and dose-dependent apoptosis in vitro. Both CI-1033 and erlotinib treatment of neuroblastoma xenograft tumors resulted in decreased tumor growth in vivo, although CI-1033 was more effective. In vivo expression of EGFR was observed predominantly in vascular endothelial cells. CONCLUSIONS: Pan-ERBB inhibition is required for ERBB-related neuroblastoma apoptosis in vitro, although EGFR contributes indirectly to tumor growth in vivo. Inhibition of EGFR in endothelial cells may be an important aspect of erlotinib's impact on neuroblastoma growth in vivo. Our results suggest that non-EGFR ERBB family members contribute directly to neuroblastoma growth and survival, and pan-ERBB inhibition represents a potential therapeutic target for treating neuroblastoma. Cancer 2010. © 2010 American Cancer Society. [source]