Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Clin Cancer Res. 2020 Jul 1;26(13):3220-3229. doi: 10.1158/1078-0432.CCR-19-3972. Epub 2020 Mar 10.
EGFR tyrosine kinase inhibitors (EGFR-TKI) benefit patients with advanced lung adenocarcinoma (ADC) harboring activating EGFR mutations. We aimed to identify biomarkers to monitor and predict the progression of patients receiving EGFR-TKIs via a comprehensive omic analysis.
We applied quantitative proteomics to generate the TKI resistance-associated pleural effusion (PE) proteome from patients with ADC with or without EGFR-TKI resistance. Candidates were selected from integrated genomic and proteomic datasets. The PE ( = 33) and serum ( = 329) levels of potential biomarkers were validated with ELISAs. Western blotting was applied to detect protein expression in tissues, PEs, and a cell line. Gene knockdown, TKI treatment, and proliferation assays were used to determine EGFR-TKI sensitivity. Progression-free survival (PFS) and overall survival (OS) were assessed to evaluate the prognostic values of the potential biomarkers.
Fifteen proteins were identified as potential biomarkers of EGFR-TKI resistance. Cadherin-3 (CDH3) was overexpressed in ADC tissues compared with normal tissues. CDH3 knockdown enhanced EGFR-TKI sensitivity in ADC cells. The PE level of soluble CDH3 (sCDH3) was increased in patients with resistance. The altered sCDH3 serum level reflected the efficacy of EGFR-TKI after 1 month of treatment ( = 43). Baseline sCDH3 was significantly associated with PFS and OS in patients with ADC after EGFR-TKI therapy ( = 76). Moreover, sCDH3 was positively associated with tumor stage in non-small cell lung cancer ( = 272).
We provide useful marker candidates for drug resistance studies. sCDH3 is a survival predictor and real-time indicator of treatment efficacy in patients with ADC treated with EGFR-TKIs.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）可使携带激活型表皮生长因子受体（EGFR）突变的晚期肺腺癌（ADC）患者获益。我们旨在通过全面的组学分析，确定用于监测和预测接受 EGFR-TKI 治疗的患者进展的生物标志物。
我们应用定量蛋白质组学技术，从具有或不具有 EGFR-TKI 耐药性的 ADC 患者的耐药性相关胸腔积液（PE）中生成 TKI 耐药相关的 PE 蛋白质组。候选物从整合的基因组和蛋白质组数据集进行选择。通过 ELISA 验证潜在生物标志物的 PE（=33）和血清（=329）水平。应用 Western blot 检测组织、PE 和细胞系中的蛋白表达。基因敲低、TKI 处理和增殖测定用于确定 EGFR-TKI 敏感性。评估无进展生存期（PFS）和总生存期（OS）以评估潜在生物标志物的预后价值。
鉴定出 15 种蛋白质作为 EGFR-TKI 耐药的潜在生物标志物。与正常组织相比，在 ADC 组织中发现钙黏蛋白-3（CDH3）过度表达。在 ADC 细胞中，CDH3 敲低增强了 EGFR-TKI 敏感性。耐药患者的 PE 中可溶性 CDH3（sCDH3）水平升高。治疗 1 个月后，sCDH3 的改变血清水平反映了 EGFR-TKI 的疗效（=43）。在接受 EGFR-TKI 治疗后，ADC 患者的基线 sCDH3与 PFS 和 OS 显著相关（=76）。此外，sCDH3 与非小细胞肺癌的肿瘤分期呈正相关（=272）。
我们提供了用于耐药性研究的有用的标记物候选物。sCDH3 是接受 EGFR-TKI 治疗的 ADC 患者的生存预测因子和治疗效果的实时指标。
