Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck

Cancer Immunology, Immunotherapy and Immunoprevention Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA
Head & Neck (Impact Factor: 2.64). 10/2010; 32(10):1412 - 1421. DOI: 10.1002/hed.21365


Cumulative evidence implicates the epidermal growth factor receptor (EGFR) as an important therapeutic target in head and neck squamous cell carcinoma (HNSCC). The basis for the lack of correlation between EGFR expression in the HNSCC tumor and clinical responses to EGFR inhibitors is incompletely understood. Although a variety of mechanisms likely contribute to the effectiveness of EGFR blockade, this review focuses on the biologic implications of known EGFR variations and the role of the immune system in mediating clinical responses to EGFR inhibitors.MethodsA Medline review of articles published in the last 10 years (1999–present) on EGFR in HNSCC was performed in combination with preliminary data from our laboratories.ResultsStudies published to date suggest no association between the expression of EGFR on HNSCC tumors and clinical responses to EGFR inhibitors. Several mechanisms have been proposed to mediate clinical response to EGFR inhibitors in HNSCC. Cumulative results from our laboratories support the role of several mechanisms, including cellular immune activation and mutated EGFR variants, in contributing to the discrepancy between level of EGFR expression and clinical response to EGFR inhibitors.Conclusion
The efficacy of EGFR targeted therapies may be mediated, at least in part, by the immune system and the presence of the truncated EGFR variant, EGFRvIII, among other factors. Criteria to identify the subset of patients likely to be responsive to EGFR targeted therapies are needed. © 2010 Wiley Periodicals, Inc. Head Neck, 2010

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    • "The importance of EGFR expression, phosphorylation, and activation of downstream effectors has been well characterized in a variety of tumor types [16] [17] [18] [19], but the role of small GTPases in mediating these important signaling cascades is not as clear. In this study, initial experiments sought to confirm EGFR expression and signaling in non-malignant human oral keratinocytes (HOK) and in a panel of well-characterized HNSCC cell lines: UM-SCC-1, UM- SCC-5, UM-SCC-6, UM-SCC-10B, UM-SCC-17B, SCC-0, and SCC-1483. "
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    ABSTRACT: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where it has been shown to promote tumor cell invasion upon phosphorylation. One mechanism by which EGFR promotes tumor progression is by activating signal cascades that lead to loss of E-cadherin, a transmembrane glycoprotein of the cell-cell adherence junctions; however mediators of these signaling cascades are not fully understood. One such mediator, RhoC, is activated upon a number of external stimuli, such as epidermal growth factor (EGF), but its role as a mediator of EGF-stimulated migration and invasion has not been elucidated in HNSCC. In the present study, we investigate the role of RhoC as a mediator of EGF-stimulated migration and invasion in HNSCC. We show that upon EGF stimulation, EGFR and RhoC were strongly activated in HNSCC. This resulted in activation of the phosphatidylinositol 3-Kinase Akt pathway (PI3K-Akt), phosphorylation of GSK-3β at the Ser9 residue, and subsequent down regulation of E-cadherin cell surface expression resulting in increased tumor cell invasion. Knockdown of RhoC restored E-cadherin expression and inhibited EGF-stimulated migration and invasion. This is the first report in HNSCC demonstrating the role RhoC plays in mediating EGF-stimulated migration and invasion by down-regulating the PI3K-Akt pathway and E-cadherin expression. RhoC may serve as a treatment target for HNSCC.
    Full-text · Article · Jan 2015 · Neoplasia (New York, N.Y.)
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    • "Recent data show versatile acitivies of cetuximab at different cellular levels and clinical response does not closely correlate with the degree of cellular overexpression of EGFR. The exact mode of action of cetuximab remains unclear [40]. Despite that cetuximab serves as an alternative to cis-platinum in clinical chemoradiation protocols for head and neck cancers. "
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    ABSTRACT: Adverse effects and hazards which have their origin from radiation using conventional techniques like 3-D conformal radiotherapy and total radiation doses are well known. However little is known about the sprectum of especially late toxicity after radiation using new technologies like intensity modulated radiotherapy (IMRT) combined with novel target volume and dose concepts. Since IMRT allows for selective protection of the large salivary glands this technique improves the intermediate term quality of life and is the standard of care despite many details need further prospective evaluation. Combining cytotoxic drugs and radiotherapy yield improved survival in well-defined high risk patients. However morbidity and mortality of these protocols are high and deserve special expertise and supportive therapy. EGF-receptor antibodies have gained well defined indications, albeit specific toxicities in combination with irradiation deserve prospective studies and special attention.
    Full-text · Article · Dec 2013
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    • "It is estimated that 33-50% of epidermal tumors present overexpression of EGFR [14], being observed in more than 90% of head and neck tumors [15]. In addition to protein overexpression, around 10-17% of the head and neck tumors present EGFR gene amplification, as shown by FISH analysis [28]. In 2006, the FDA approved the use of cetuximab, a chimeric anti-EGFR mAb, for the treatment of patients with head and neck tumors presenting overexpression of this protein. "
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    ABSTRACT: Background Esophageal squamous cell carcinoma (ESCC) shows a 5-year survival rate below 10%, demonstrating the urgency in improving its treatment. Alterations in epidermal growth factor receptors are closely related to malignancy transformation in a number of tumors and recent successful targeted therapies have been directed to these molecules. Therefore, in this study, we analyzed the expression of EGFR and HER2 and evaluated EGFR mutation profile as well as the presence of mutations in hotspots of KRAS and BRAF in ESCC patients. Methods We performed RT-qPCR, immunohistochemistry and Fluorescent in situ hybridization to determine EGFR and HER2 expression in ESCC patients, and direct sequencing and PCR-RFLP for mutations and polymorphism analysis. Results Our results showed an increased EGFR mRNA expression in tumors compared to surrounding tissue (p <0.05), with 11% of the cases presenting at least a four-fold difference between tumor and paired adjacent mucosa. EGFR protein overexpression was present only in 4% of the cases. The median expression of HER2 mRNA was not different between tumors and adjacent mucosa. Still, 7% of the tumors presented at least a 25-fold higher expression of this gene when compared to its paired counterpart. Immunohistochemical analysis revealed that 21% of the tumors were positive for HER2 (scores 2+ and 3+), although only 3+ tumors presented amplification of this gene. Mutation analysis for EGFR (exons 18-21), KRAS (codons 12 and 13) and BRAF (V600E) showed no mutations in any of the hotspots of these genes in almost 100 patients analyzed. EGFR presented synonymous polymorphisms at codon 836 (C>T) in 2.1% of the patients, and at codon 787 (G>A) in 79.2% of the cases. This last polymorphism was also evaluated in 304 healthy controls, which presented a similar frequency (73.7%) in comparison with ESCC patients. The absence of mutations of EGFR, KRAS and BRAF as well as the overexpression of EGFR and HER2 in less than 10% of the patients suggest that this signaling pathway is altered in only a small proportion of patients with ESCC. Conclusion HER receptors target therapies may have the potential to be effective in only a minor fraction of patients with ESCC.
    Full-text · Article · Dec 2012 · BMC Cancer
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