表皮生长因子受体酪氨酸激酶抑制剂的敏感性需要食管癌和恶性胸膜间皮瘤中的 E-钙黏蛋白。
Sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor requires E-cadherin in esophageal cancer and malignant pleural mesothelioma.
机构信息
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
出版信息
Anticancer Res. 2013 Jun;33(6):2401-8.
BACKGROUND/AIM: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has limited anticancer efficacy in EGFR-positive esophageal cancer (EsC) and malignant mesothelioma (MPM). The underlying molecular mechanism of resistance to EGFR-TKI in these types of cancer remains unclear.
MATERIALS AND METHODS
We tested sensitivity to EGFR-TKI, expression/activity of common signal transduction pathways and epithelial to mesenchymal transition (EMT) gene signatures in 14 EsC and MPM cultured cell lines in vitro.
RESULTS
More than 50% EGFR-positive EsC and MPM cells were resistant to EGFR-TKI, and susceptibility to EGFR-TKI growth-inhibitory effect correlated positively with expression of E-cadherin (epithelial gene marker) and negatively with mesenchymal gene markers. Acquired resistance to EGFR-TKI in intrinsically sensitive cancer cells coincided with spontaneous loss of E-cadherin, while ectopic expression of E-cadherin sensitized resistant cells to EGFR-TKI.
CONCLUSION
E-Cadherin expression appears to be not only a strong biomarker but also a functional requirement and potential therapeutic target for sensitivity to EGFR-TKI.
背景/目的：表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）在 EGFR 阳性食管癌（EsC）和恶性间皮瘤（MPM）中的抗癌疗效有限。这些类型的癌症对 EGFR-TKI 产生耐药性的潜在分子机制尚不清楚。
材料和方法
我们在体外测试了 14 种 EsC 和 MPM 培养细胞系对 EGFR-TKI 的敏感性、常见信号转导通路的表达/活性以及上皮到间充质转化（EMT）基因特征。
结果
超过 50%的 EGFR 阳性 EsC 和 MPM 细胞对 EGFR-TKI 耐药，对 EGFR-TKI 生长抑制作用的敏感性与 E-钙黏蛋白（上皮基因标志物）的表达呈正相关，与间充质基因标志物呈负相关。内在敏感癌细胞对 EGFR-TKI 的获得性耐药与 E-钙黏蛋白的自发缺失同时发生，而 E-钙黏蛋白的异位表达使耐药细胞对 EGFR-TKI 敏感。
结论
E-钙黏蛋白的表达似乎不仅是一个强有力的生物标志物，也是对 EGFR-TKI 敏感性的功能要求和潜在治疗靶点。
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