title: Global protein profiling reveals anti-EGFR monoclonal antibody 806-modulated proteins in A431 tumor xenografts.
abstract: An important mediator of tumorigenesis, the epidermal growth factor receptor (EGFR) is expressed in almost all non-transformed cell types, associated with tumor progression, angiogenesis and metastasis. The significance of the EGFR as a cancer therapeutic target is underscored by the clinical development of several different classes of EGFR antagonists, including monoclonal antibodies (mAb) and tyrosine kinase inhibitors. Extensive preclinical studies have demonstrated the anti-tumor effects of mAb806 against tumor xenografts overexpressing EGFR. EGF stimulation of A431 cells induces rapid tyrosine phosphorylation of intracellular signalling proteins which regulate cell proliferation and apoptosis. Detailed understanding of the intracellular signalling pathways and components modulated by mAbs (such as mAb806) to EGFR, and other growth factor receptors, remain limited. The use of fluorescence 2D difference gel electrophoresis (2D DIGE), coupled with sensitive MS-based protein profiling in A431 tumor (epidermoid carcinoma) xenografts, in combination with mAb806, revealed proteins modulating endocytosis, cell architecture, apoptosis, cell signalling pathways and cell cycle regulation, including Dynamin-1-like protein, cofilin-1 protein, and 14-3-3 protein zeta/delta. Further, we report various proteins, including Interferon-induced protein 53 (IFI53), and Oncogene EMS1 (EMS1) which have roles in the tumor microenvironment, regulating cancer cell invasiveness, angiogenesis and formation of metastases. These findings contribute to understanding the underlying biological processes associated with mAb806 therapy of EGFR-positive tumors, and identifying further potential protein markers that may contribute in assessment of the treatment response.
authors: Ludwig Institute for Cancer Research , Victoria , Australia .
authors: Sze Ting
authors: ST
authors: Lee
authors: Hong
authors: H
authors: Ji
authors: David W
authors: DW
authors: Greening
authors: Robert W H
authors: RW
authors: Speirs
authors: Angela
authors: A
authors: Rigopoulos
authors: Vinochani
authors: V
authors: Pillay
authors: Carmel
authors: C
authors: Murone
authors: Angela
authors: A
authors: Vitali
authors: Kai
authors: K
authors: Stühler
authors: Terrance G
authors: TG
authors: Johns
authors: Georgia A
authors: GA
authors: Corner
authors: John M
authors: JM
authors: Mariadason
authors: Richard J
authors: RJ
authors: Simpson
authors: Andrew M
authors: AM
authors: Scott
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D009363:Neoplasm Proteins; D066246:ErbB Receptors