EGF mutant receptor vIII as a molecular target in cancer therapy.

Kuan, Chien-Tsun; Wikstrand, Carol J.; Bigner, Darell D.

doi:10.1677/erc.0.0080083

Cited by 296 publications

(231 citation statements)

References 48 publications

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“…Among patients with recurrent malignant glioma, response to EGFR inhibitors was observed in a subset of patients despite the lack of mutations in the EGFR kinase domain, and such a response was correlated with loss of PTEN and expression of EGFR class III variant (EGFRvIII), a mutant form of EGFR that lacks 267 amino acids from its extracellular domain. 46,47 In conclusion, expression of EGFR and/or ErbB-2 can be detected in a sizeable subset of rhabdomyosarcoma tumors, with no evidence of amplification at 7p11.2 and 17q12 or mutations in the EGFR tyrosine kinase domain. Notably, EGFR expression correlates with the embryonal subtype independent of other variables such as stage, age, and gender, and it is also more likely to coexpress EGFR and ErbB-2.…”

Section: Discussionmentioning

confidence: 79%

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

et al. 2006

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Both epidermal growth factor receptor (EGFR) and ErbB-2 play an important role in cancer biology and constitute promising molecular targets of therapy. EGFR and ErbB-2 expression has been observed in rhabdomyosarcoma cell lines but not analyzed systematically in rhabdomyosarcoma tumors. Tissue microarray sections representing 66 rhabdomyosarcoma tumors (34 embryonal rhabdomyosarcoma, 32 alveolar rhabdomyosarcoma) were surveyed by immunohistochemistry using antibodies specific for EGFR and ErbB-2. Immunostains were assessed for intensity (0: no immunostaining; 1: weak; 2: moderate; 3: strong) and percentage of at least 500 neoplastic cells exhibiting membranous or membranous and cytoplasmic immunostaining. EGFR and ErbB-2 expression was considered positive if the product of intensity and percentage was greater than 10. Patients had a median age of 5.7 years (range 8 months-19.1 years), and of 65/ 66 patients, 38 were males and 27 were females. Expression of ErbB-2 was identified in 22/66 (33%) cases and tended to be more frequent in the alveolar subtype (13/32, 41%, vs 9/34, 26%, P ¼ 0.30). Expression of EGFR was identified in 31/66 (47%) cases and correlated with the embryonal subtype (26/34, 76%, vs 5/32, 16%, Po0.0001) independent of stage, age, and gender. Coexpression of EGFR and ErbB-2 was identified in eight tumors, of which six were embryonal rhabdomyosarcoma. None of the cases exhibited EGFR or ErbB-2 gene amplification, as assessed using fluorescence in situ hybridization. Furthermore, analysis of 11 additional rhabdomyosarcoma tumors (six alveolar; five embryonal) revealed no evidence of mutations in EGFR exons 18, 19, 20, and 21. In summary, expression of EGFR and/or ErbB-2 is detected in a sizeable subset of rhabdomyosarcoma tumors without evidence of EGFR or ErbB-2 amplification or mutations in the EGFR tyrosine kinase domain. Notably, expression of EGFR correlates with the embryonal subtype, which is also more likely to coexpress EGFR and ErbB-2.

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Section: Discussionmentioning

confidence: 79%

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

et al. 2006

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“…40 One of the most common EGFR mutations, EGFRvIII, involves an in-frame deletion of exons 2-7 with resultant loss of residues 6-273 in the extracellular domain, which leads to constitutive activation of the receptor and resistance to downregulation by endocytosis. 41 This mutation is predominantly encountered in glioblastomas with high-level gene amplifications as well. EGFR signals may also be enhanced by increased levels of receptor ligands (such as EGF, TGF-a, or amphiregulin).…”

Section: Discussionmentioning

confidence: 99%

Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

et al. 2006

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Immunohistochemical detection of expression of the epidermal growth factor receptor (EGFR) has been utilized to identify eligible patients with solid malignant tumors, including colorectal adenocarcinoma, for monoclonal antibody therapy (eg, cetuximab). The EGFR status in squamous cell carcinoma of the anal canal, an uncommon malignancy traditionally treated with chemoradiation, has not been well investigated. In this study, 38 primary squamous cell carcinomas of the anal canal were immunohistochemically examined for EGFR expression and analyzed by fluorescence in situ hybridization (FISH) for EGFR gene copy numbers. The results showed a variable degree of EGFR expression in 21 (55%) tumors, among which 13 (62%) cases exhibited a 2 þ to 3 þ staining pattern according to the Dako EGFR phamDx interpretation guide. There were no significant differences among tumors stratified by stage, degree of keratinization, or tissue block storage times. FISH analysis showed that none of the 34 cases with interpretable results had EGFR gene amplification. Increased gene copy numbers due to polysomy 7 were seen in seven of 18 (39%) cases that expressed EGFR protein and four of 16 (25%) cases that did not (P ¼ 0.3876). Ten (56%) tumors with positive EGFR staining showed a balanced disomy 7 pattern and one case with monosomy 7 exhibited strong EGFR expression (3 þ ). These results demonstrate that EGFR is overexpressed in more than one-half of the squamous cell carcinomas of the anal canal through mechanisms other than gene amplification. These observations may have important therapeutic implications since EGFR-based targeted therapies have shown promise for other malignant neoplasms.

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“…EGFR is, in fact, frequently overexpressed in human tumors such as head and neck squamous cell carcinoma (HNSCC), glioblastoma, non-small cell lung cancer (NSCLC), and breast, colorectal (CRC), bladder, prostate and ovarian carcinomas (Salomon et al 1995, Mendelsohn 2001. The type-III mutated variant of the human EGFR, denominated EGFRvIII and characterized by a deletion in the extracellular domain that leads to constitutive activation of its tyrosine kinase (TK) domain, is the most frequently expressed EGFR genetic alteration in some cancers, like glioblastomas (Nishikawa et al 1994, Moscatello et al 1995, Kuan et al 2001.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic and acquired resistance to EGFR inhibitors in human cancer therapy

Bianco¹,

Troiani²,

Ciardiello³

2005

Endocr Relat Cancer

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The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer since it contributes to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Among a variety of approaches used to target EGFR signaling, EGFR blocking monoclonal antibodies and small molecular weight EGFR tyrosine kinase compounds have been successfully developed. The results of a large body of preclinical studies and clinical trials suggest that targeting the EGFR could represent a significant contribution to cancer therapy. Both types of agent exert a significant antiproliferative activity when used alone or in combination with conventional antitumor treatments, such as chemotherapy or radiation therapy. Although the advanced clinical development of EGFR blocking drugs demonstrates their efficacy in some human metastatic diseases, such as lung, head and neck and colorectal cancers, the issue of constitutive resistance in a large number of patients and the development of acquired resistance in the responders remains an unexplored subject of investigation. Recent evidence suggests the role of specific activating mutations within the tyrosine kinase domain of EGFR to explain the dramatic responses to small molecule tyrosine kinase inhibitors in a subgroup of lung cancer patients. However, the intrinsic molecular mechanisms of resistance to these drugs are still unclear. This review will focus on the preclinical findings on therapeutic resistance to EGFR targeting agents. Endocrine-Related Cancer (2005) 12 S159-S171

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EGF mutant receptor vIII as a molecular target in cancer therapy.

Cited by 296 publications

References 48 publications

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

Intrinsic and acquired resistance to EGFR inhibitors in human cancer therapy

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