Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>A circulating isoform of EGFR has been identified as an emerging serum biomarker in cancer patients. Serum concentrations of EGFR have been evaluated as screening, diagnostic, prognostic, and theragnostic markers for diverse human malignancies, including breast, ovarian, endometrial, colorectal, and lung cancer. Yet full-length EGFR is rarely shed from normal or malignant cells. Here we demonstrate that an alternately spliced EGFR isoform, termed ‘sEGFR,’ gives rise to the circulating sEGFR protein through proteolytic cleavage of a cell surface precursor. This cleavage event is inhibited by fibronectin and stimulated by both an anti-Δ5/α1 integrin antibody and the metalloprotease activator 4-aminophenylmercuric acetate. Preliminary results identify ADAM17/TACE as at least one mediator of sEGFR shedding. Shed sEGFR binds to EGF with high affinity. Two FDA-approved therapeutic anti-EGFR antibodies, cetuximab (Erbitux) and panitumumab (Vectibix), inhibit shedding of sEGFR, implicating sEGFR as a potential alternative target for these antibodies, consistent with previous studies indicating that baseline serum sEGFR concentrations may predict responsiveness to anti-EGFR-targeted therapy. These observations bear striking similarity to aspects of trastuzumab regulation of HER2, shedding, and, by analogy, may have implications for the design of future clinical trials using EGFR-directed therapeutics, including cetuximab and panitumimab.</jats:p>
<jats:p>Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3624. doi:1538-7445.AM2012-3624</jats:p>