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Shedding of Soluble Epidermal Growth Factor Receptor (sEGFR) Is Mediated by a Metalloprotease/Fibronectin/Integrin Axis and Inhibited by Cetuximab

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posted on 02.07.2013, 00:00 by Jason A. Wilken, Marianela Perez-Torres, Rene Nieves-Alicea, Elsa M. Cora, Trace A. Christensen, Andre T. Baron, Nita J. Maihle
Soluble epidermal growth factor receptor (sEGFR) is a circulating serum biomarker in cancer patients. Recent studies suggest that baseline serum sEGFR concentrations may predict responsiveness to EGFR-targeted therapy. Here, we demonstrate that sEGFR is generated through proteolytic cleavage of a cell surface precursor of an alternately spliced EGF receptor isoform and that sEGFR binds to EGF with high affinity. Proteolytic cleavage is stimulated by an anti-α5/β1 integrin antibody and 4-aminophenylmercuric acetate, and inhibited by fibronectin. Two FDA-approved therapeutic anti-EGFR antibodies also inhibit shedding of sEGFR, thus implicating the cell surface precursor of sEGFR as a competing target for anti-EGFR antibodies in human tissues. These observations parallel trastuzumab regulation of HER2 shedding and have implications for patient stratification in future clinical trials of EGFR-targeted antibodies.

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