Journal
BIOCHEMISTRY
Volume 52, Issue 26, Pages 4531-4540Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi400437d
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Funding
- Susan G. Komen for the Cure
- Ovarian Cancer Research Fund
- Marsha Rivkin Center for Ovarian Cancer Research
- NIH [SC2GM084789, CA 79808]
- NIH/COBRE [P20RR016439]
- Kentucky Lung Cancer Research Program (KLCR) [05-08]
- Markey Cancer Center Translational Research Program
- Senior Women in Medicine Professorship from Yale University School of Medicine
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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-alpha 5/beta 1 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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