Cancer Biotherapy Center, The First Affiliated Hospital of Nanjing Medical University, China.
Biomed Pharmacother. 2010 Feb;64(2):88-92. doi: 10.1016/j.biopha.2009.06.010. Epub 2009 Oct 23.
Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC). According to statistics, NSCLC patients who are female, have adenocarcinoma, or never smoked have a higher response rate to gefitinib treatment. This phenomenon could be due to the interaction between the estrogen receptor (ER) and EGFR. To test whether inhibition of the EGFR signaling pathway affects the antitumour effect of gefitinib, NSCLC cell lines were treated with gefitinib and tamoxifen, an ER antagonist. Cotreatment with gefitinib plus tamoxifen decreased the proliferation and increased the apoptosis of A549 and H1650 adencarcinoma cell lines, when compared with either drug alone. However, there was no effect on H520 cells (squamous cell carcinoma). Rapid activation of the EGFR pathway by both EGF and beta-E2 was observed in A549 cells. Additionally, EGFR and ERbeta expression was down-regulated in response to estrogen and EGF, respectively, but up-regulated in response to tamoxifen and genfitib, respectively. These results suggest that there is a functional cross-signaling between the EGFR and the ER pathways in NSCLC, possibly providing a rationale to combine gefitinib with anti-estrogen therapy for lung cancer treatment.
吉非替尼是一种表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，已被批准用于治疗非小细胞肺癌（NSCLC）。据统计，女性、腺癌或从不吸烟的 NSCLC 患者对吉非替尼治疗的反应率更高。这种现象可能是由于雌激素受体（ER）和 EGFR 之间的相互作用。为了测试 EGFR 信号通路的抑制是否会影响吉非替尼的抗肿瘤作用，用吉非替尼和他莫昔芬（一种 ER 拮抗剂）处理 NSCLC 细胞系。与单独使用任一药物相比，吉非替尼加他莫昔芬联合治疗可降低 A549 和 H1650 腺癌细胞系的增殖并增加其凋亡。然而，对 H520 细胞（鳞状细胞癌）没有影响。在 A549 细胞中观察到 EGFR 通路被 EGF 和 β-E2 迅速激活。此外，EGFR 和 ERβ表达分别对雌激素和 EGF 作出反应而被下调，但分别对他莫昔芬和吉非替尼作出反应而被上调。这些结果表明，NSCLC 中 EGFR 和 ER 途径之间存在功能交叉信号，可能为联合使用吉非替尼和抗雌激素治疗肺癌提供依据。
