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.
Biochemistry. 2013 Jul 2;52(26):4531-40. doi: 10.1021/bi400437d. Epub 2013 Jun 21.
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.
可溶性表皮生长因子受体 (sEGFR) 是癌症患者循环血清中的生物标志物。最近的研究表明，基线血清 sEGFR 浓度可能预测对 EGFR 靶向治疗的反应性。在这里，我们证明 sEGFR 是通过切割 EGFR 同种型的细胞表面前体蛋白产生的，并且 sEGFR 与 EGF 具有高亲和力结合。蛋白水解切割受抗 α5/β1 整合素抗体和 4-氨基苯汞乙酸盐的刺激，并受纤维连接蛋白抑制。两种已获 FDA 批准的治疗性抗 EGFR 抗体也抑制 sEGFR 的脱落，因此 sEGFR 的细胞表面前体可能是人类组织中抗 EGFR 抗体的竞争靶标。这些观察结果与曲妥珠单抗对 HER2 脱落的调节相似，对未来 EGFR 靶向抗体临床试验中的患者分层具有重要意义。
