Global protein profiling reveals anti-EGFR monoclonal antibody 806-modulated proteins in A431 tumor xenografts
journal contributionposted on 13.08.2021, 01:35 authored by Sze LeeSze Lee, H Ji, David GreeningDavid Greening, RWH Speirs, Angela RigopoulosAngela Rigopoulos, V Pillay, C Murone, A Vitali, K Stühler, TG Johns, GA Corner, John MariadasonJohn Mariadason, Richard SimpsonRichard Simpson, Andrew ScottAndrew Scott
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. © 2013 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.
Funding was provided by the Australian National Health and Medical Research Council under Program Grant #487922, and NHMRC Project Grant #234709. We acknowledge the NHMRC-funded Australian Proteomics Computational Facility (APCF) under Enabling Grant #381413. This work was supported, in part, by funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia. We acknowledge the Australian Cancer Research Foundation for providing funds to purchase the Orbitrap (TM) mass spectrometer. Andrew M. Scott and Terrance G. Johns are inventors on patents for mAb806.
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Science & TechnologyLife Sciences & BiomedicineCell BiologyEndocrinology & Metabolism2D-DIGEanimal modelmAb806A431cancerEGFRxenograftapoptosistumor microenvironmentGROWTH-FACTOR RECEPTORCANCER CELLSLIM-KINASEIN-VIVOPHASE-IPHOSPHORYLATIONMONOCLONAL-ANTIBODY-80614-3-3-ZETAACTIVATIONPROTEOMICSCell Line, TumorAnimalsMice, Inbred BALB CHumansMiceCarcinoma, Squamous CellNeoplasm ProteinsAntibodies, MonoclonalXenograft Model Antitumor AssaysGene Expression Regulation, NeoplasticFemaleCarcinogenesisErbB ReceptorsBiochemistry & Molecular Biology