Epidermal growth factor receptor mutation type iii transfected into a small cell lung cancer cell line is predominantly localized at the cell surface and enhances the malignant phenotype

Damstrup, Lars; Pedersen, Mikkel Wandahl; Bastholm, Lone; Elling, Folmer; Poulsen, Hans Skovgaard

doi:10.1002/ijc.1572

Cited by 35 publications

(31 citation statements)

References 41 publications

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“…Despite being unable to bind growth factors, this variant is constitutively phosphorylated and elicits downstream signaling qualitatively and quantitatively different from ligand-activated wild-type EGFR (Pedersen et al, 2001). EGFRvIII confers enhanced tumorigenicity (Damstrup et al, 2002) and has been detected, for example, in gliomas (57-86%) and in non-small cell lung cancer (NSCLC) (5-39%) (Moscatello et al, 1995;Okamoto et al, 2003;Ji et al, 2006).…”

Section: Egfr and Cancermentioning

confidence: 99%

EGFR kinase domain mutations – functional impact and relevance for lung cancer therapy

2007

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In 2004 remarkable clinical responses in non-small-cell lung cancer (NSCLC) patients treated with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib were reported to correlate with the presence of certain somatic EGFR kinase domain mutations in tumors. Since then, a surge of enthusiasm has been encountered in the field of molecular and clinical oncology. Beyond the promise of a tailored medicine, questions about the molecular mechanisms underlying the observed effects have arisen. In vitro analysis of NSCLC cells with endogenous EGFR mutations, recombinant expression of EGFR variants by transfection of several cell lines and the generation of transgenic mice expressing mutant EGFR were applied to study the impact of these genetic alterations on cellular signaling and cell fate. This review outlines the current mechanistic knowledge derived from such studies and discusses the relevance of EGFR kinase domain mutations for EGFR-directed therapies, including monoclonal antibodies.

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Section: Egfr and Cancermentioning

confidence: 99%

EGFR kinase domain mutations – functional impact and relevance for lung cancer therapy

2007

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“…[1][2] This mutant receptor is a constitutively activated, ligand-independent oncoprotein and has been detected in a variety of human cancers. [3][4][5][6][7][8] Early studies have shown that EGFRvIII appears to utilize downstream signaling pathways in a different manner from those of wild-type EGFR. [9][10][11][12] Furthermore, EGFR-overexpressing xenografts were sensitive to treatment with gefitinib (ZD1839), an EGFR-tyrosine kinase inhibitor, while EGFRvIII-expressing xenografts failed to respond to gefitinib treatment.…”

Section: Introductionmentioning

confidence: 99%

Hypophosphorylation of residue Y1045 leads to defective downregulation of EGFRvIII

Han

Zhang²,

Yu³

et al. 2006

Cancer Biology & Therapy

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Downregulation of the EGF receptor is the net result of receptor degradation and recycling. Cbl functions by specifically targeting activated ErbB receptors for ubiquitination, facilitating ligand-induced desensitization of EGFR. The interaction between EGFR and c-Cbl has been shown to depend upon receptor phosphorylation at tyrosine residue 1045, the major docking site for c-Cbl. To better understand the biological consequences of EGFR mutants in human cancers, we compared wild-type EGFR and EGFRvIII internalization, as well as gefitinib sensitive and resistant EGFR kinase mutations found in non-small cell lung carcinoma. We observed that Cbl failed to associate with EGFRvIII as well as an inability of the receptor to undergo ubiquitination and degradation. The most intriguing observation is that EGFRvIII tyrosine 1045 residue is either un-phosphorylated or hypophosphorylated. This is in contrast to other tyrosine residues in EGFRvIII, such as Y1173, which exhibit levels of phosphorylation comparable to those of wild-type EGFR. These results suggest that hypophosphorylation of tyrosine residue 1045 is likely to be the cause for EGFRvIII escape from c-Cbl-induced ubiquitination and degradation, enhancing EGFRvIII's ability to increase proliferation in breast cancer cells. Interestingly, inefficient degradation was only observed in the gefitinib resistant EGFR kinase mutant, despite the fact that this mutant receptor is capable of recruiting c-Cbl and undergoes ubiquitination. The gefitinib sensitive EGFR kinase mutant exhibits similar ubiquitination and degradation patterns as the wild-type EGFR. Collectively, different EGFR mutations exert various negative mechanisms that have the potential to modify receptor internalization and degradation, and may play a critical role in resistance to tyrosine kinase inhibitory treatments.

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“…The EGFRvIII is also capable of significantly enhancing the tumorgenicity of immortalized murine fibroblasts Moscatello et al, 1996) and the breast cancer cell line MCF-7 (Tang et al, 2000). Also, the EGFRvIII increases the in vitro invasiveness of a smallcell lung cancer cell line (Damstrup et al, 2002). Using the murine hematopoietic 32D cell line, Tang et al (2000) demonstrated that the EGFRvIII is capable of directly transforming a non-tumorigenic cell line.…”

Section: Introductionmentioning

confidence: 99%

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

et al. 2006

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The overexpression or mutation of tyrosine kinases (TKs), such as the epidermal growth factor receptor (EGFR), can lead to the development of cancer. The most common mutation of the EGFR in glioblastomas is the deletion of exons 2-7 known as the EGFRvIII. This mutant receptor cannot bind EGF but, instead, is constitutively active. The Cbl family of ubiquitin ligases (Cbl, Cbl-b, and Cbl-c) targets the activated EGFR for degradation. As the EGFRvIII is transforming, we investigated whether it could be downregulated by the Cbl proteins. The over-expression of all three Cbl proteins resulted in the ubiquitination and degradation of the EGFRvIII. As with the wild-type EGFR, the TK-binding domain and the RING finger of Cbl-b are sufficient for the downregulation of the EGFRvIII. Also, we found that Cbl-b is recruited to the EGFRvIII and inhibits the transformation of NIH 3T3 cells by the EGFRvIII. Mutation of the Cbl-binding site (Y1045F) in the EGFRvIII inhibits its ubiquitination and downregulation by Cbl-b and enhances its ability to transform. Furthermore, the EGFR TK inhibitor, AG 1478, prevents the downregulation of the EGFRvIII by the Cbl proteins and antagonizes the ability of an immunotoxin directed against the EGFRvIII to kill cells expressing this receptor. In conclusion, the EGFR-vIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRvIII immunotoxins.

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Epidermal growth factor receptor mutation type iii transfected into a small cell lung cancer cell line is predominantly localized at the cell surface and enhances the malignant phenotype

Cited by 35 publications

References 41 publications

EGFR kinase domain mutations – functional impact and relevance for lung cancer therapy

EGFR kinase domain mutations – functional impact and relevance for lung cancer therapy

Hypophosphorylation of residue Y1045 leads to defective downregulation of EGFRvIII

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

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