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Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-kappaB and initiates tumour vascular normalization.

ABSTRACT: Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), which is often pathogenetically overexpressed or mutated in epithelial malignancies and glioma, have been modestly successful, with some approved for human use. MAb 806 was raised against de2-7EGFR (or EGFRvIII), a constitutively active mutation expressed in gliomas, but also recognizes a subset (<10%) of wild-type (wt) EGFR when it is activated by autocrine loop, overexpression or mutation. It does not bind inactive EGFR in normal tissues like liver. Glioma xenografts expressing the de2-7EGFR treated with mAb 806 show reduced receptor autophosphorylation, increased p27(KIP1) and reduced cell proliferation. Xenografts expressing the wtEGFR activated by overexpression or autocrine ligand are also inhibited by mAb 806, but the mechanism of inhibition has been difficult to elucidate, especially because mAb 806 does not prevent wtEGFR phosphorylation or downstream signalling in vitro. Thus, we examined the effects of mAb 806 on A431 xenograft angiogenesis. MAb 806 increases vascular endothelial growth factor (VEGF) and interleukin-8 production by activating NF-kappaB and normalizes tumour vasculature. Pharmacological inhibition of NF-kappaB completely abrogated mAb 806 activity, demonstrating that NF-kappaB activation is necessary for its anti-tumour function in xenografts. Given the increase in VEGF, we combined mAb 806 with bevacizumab in vivo, resulting in additive activity.

SUBMITTER: Gan HK

PROVIDER: S-EPMC4516546 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-kappaB and initiates tumour vascular normalization.

Gan Hui K HK Lappas Martha M Cao Diana X DX Cvrljevdic Anna A Scott Andrew M AM Johns Terrance G TG

Journal of cellular and molecular medicine 20090511 9B

Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), which is often pathogenetically overexpressed or mutated in epithelial malignancies and glioma, have been modestly successful, with some approved for human use. MAb 806 was raised against de2-7EGFR (or EGFRvIII), a constitutively active mutation expressed in gliomas, but also recognizes a subset (<10%) of wild-type (wt) EGFR when it is activated by autocrine loop, overexpression or ...[more]

PMID: 19432811

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Project description:MET expression is elevated in a majority of human skin cancers but its contributions to pathogenesis have not been evaluated. In a mouse model of constitutive overexpression of HGF (MT-HGF), the incidence of squamous cell skin tumors induced by initiation with 7,12-dimethylbenz(a)anthracene (DMBA) followed by exposure to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) is increased fivefold over control groups. Half of these tumors carry Hras1 or Kras mutations. Without DMBA initiation, tumors also erupt on MT-HGF mouse skin but only when TPA promotion is enhanced by crossing these mice with mice overexpressing cutaneous PKCα. None of these tumors have Ras mutations. In culture, MT-HGF keratinocytes share identical MET mediated phenotypic and biochemical features with wildtype keratinocytes transformed by oncogenic RAS. In both cell types, these common features of initiated keratinocytes arise from autocrine activation of EGFR through elevated expression and release of EGFR ligands. Inhibition of EGFR ablates the initiated signature of MT-HGF keratinocytes in vitro and causes regression of MT-HGF induced tumors in vivo. Global gene expression data indicate that MT-HGF and RAS transformed keratinocytes share largely an identical profile of over 5000 mRNAs. Gene ontology analysis reveals the most affected concordant signature is enriched for functions relevant to tissue development and response to wounding, accompanied by cytokine and growth factor activity, and peptidase and endopeptidase activity previously not linked to initiated keratinocytes. Furthermore, gene co-expression analysis in skin cancer patients revealed a core RAS/MET co-expression network considerably activated in pre cancerous and cancerous lesions. Thus MET activation though EGFR contributes to human cutaneous cancers, and inhibitors could be efficacious in advanced lesions such as those seen in transplant recipient patients. In this dataset with provide gene expression data from primary mouse keratinocytes in culture.

Dataset Information

Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-kappaB and initiates tumour vascular normalization.

Publications

Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-kappaB and initiates tumour vascular normalization.

Similar Datasets

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