Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab

Jason A. Wilken, Marianela Perez-Torres, Rene Nieves-Alicea, Elsa M. Cora, Trace A. Christensen, Andre T. Baron, Nita J. Maihle

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4531-4540
Number of pages10
JournalBiochemistry
Volume52
Issue number26
DOIs
StatePublished - Jul 2 2013

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Metalloproteases
Fibronectins
Epidermal Growth Factor Receptor
Integrins
Antibodies
Anti-Idiotypic Antibodies
Biomarkers
Tumor Biomarkers
Cetuximab
Serum
Epidermal Growth Factor
Protein Isoforms
Clinical Trials
Tissue
Therapeutics

ASJC Scopus subject areas

  • Biochemistry

Cite this

Wilken, J. A., Perez-Torres, M., Nieves-Alicea, R., Cora, E. M., Christensen, T. A., Baron, A. T., & Maihle, N. J. (2013). Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab. Biochemistry, 52(26), 4531-4540. https://doi.org/10.1021/bi400437d

Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab. / Wilken, Jason A.; Perez-Torres, Marianela; Nieves-Alicea, Rene; Cora, Elsa M.; Christensen, Trace A.; Baron, Andre T.; Maihle, Nita J.

In: Biochemistry, Vol. 52, No. 26, 02.07.2013, p. 4531-4540.

Research output: Contribution to journalArticle

Wilken, JA, Perez-Torres, M, Nieves-Alicea, R, Cora, EM, Christensen, TA, Baron, AT & Maihle, NJ 2013, 'Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab', Biochemistry, vol. 52, no. 26, pp. 4531-4540. https://doi.org/10.1021/bi400437d
Wilken, Jason A. ; Perez-Torres, Marianela ; Nieves-Alicea, Rene ; Cora, Elsa M. ; Christensen, Trace A. ; Baron, Andre T. ; Maihle, Nita J. / Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab. In: Biochemistry. 2013 ; Vol. 52, No. 26. pp. 4531-4540.
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