Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab.
Enviado por Marianela Perez-Torres el
Título | Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Autores | Wilken, JA, Perez-Torres, M, Nieves-Alicea, R, Cora, EM, Christensen, TA, Baron, AT, Maihle, NJ |
Journal | Biochemistry |
Volume | 52 |
Issue | 26 |
Pagination | 4531-40 |
Date Published | 2013 Jul 2 |
ISSN | 1520-4995 |
Palabras clave | Alternative Splicing, Animals, Antibodies, Anti-Idiotypic, Antibodies, Monoclonal, Humanized, CHO Cells, Clinical Trials as Topic, Cricetinae, Epidermal Growth Factor, Humans, Integrins, Neoplasms, Neoplastic Cells, Circulating, Protein Isoforms, Receptor, Epidermal Growth Factor, Tumor Markers, Biological |
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. |
DOI | 10.1021/bi400437d |
Alternate Journal | Biochemistry |
PubMed ID | 23731208 |
Grant List | CA 79808 / CA / NCI NIH HHS / United States P20RR016439 / RR / NCRR NIH HHS / United States R01 CA079808 / CA / NCI NIH HHS / United States SC2 GM084789 / GM / NIGMS NIH HHS / United States |