title: Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab.
abstract: 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.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, PO Box 208063, 310 Cedar Street, FMB 211, New Haven, Connecticut 06520-8063, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wilken
authors.forename: Marianela
authors.initials: M
authors.lastname: Perez-Torres
authors.forename: Rene
authors.initials: R
authors.lastname: Nieves-Alicea
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Cora
authors.forename: Trace A
authors.initials: TA
authors.lastname: Christensen
authors.forename: Andre T
authors.initials: AT
authors.lastname: Baron
authors.forename: Nita J
authors.initials: NJ
authors.lastname: Maihle
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000737:chemistry; D016466:CHO Cells; D000068818:Cetuximab; D002986:Clinical Trials as Topic; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000378:metabolism; D066246:ErbB Receptors / Q000097:blood / Q000737:chemistry; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D009360:Neoplastic Cells, Circulating / Q000737:chemistry*; D020033:Protein Isoforms / Q000737:chemistry
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D016023:Integrins; D020033:Protein Isoforms; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab