| 张可人,仰昳婕,黄华艳,张义朋,朱 亮.靶向AXL克服肺腺癌EGFR-TKIs获得性耐药[J].现代生物医学进展英文版,2019,19(18):3449-3455. |
| 靶向AXL克服肺腺癌EGFR-TKIs获得性耐药 |
| Targeting AXL Overcomes Acquired Resistance to EGFR-TKIs in Lung Adenocarcinomas |
| Received:February 23, 2019 Revised:March 15, 2019 |
| DOI：10.13241/j.cnki.pmb.2019.18.010 |
| 中文关键词: 肺腺癌 AXL EGFR-TKI 耐药 |
| 英文关键词: Lung adenocarcinoma AXL EGFR-TKI Resistance |
| 基金项目:国家自然科学基金项目（81872882；81573018） |
| Author Name | Affiliation | E-mail | | ZHANG Ke-ren | Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China | hedgehog2016@sjtu.edu.cn | | YANG Yi-jie | Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China | | | HUANG Hua-yan | Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China | | | ZHANG Yi-peng | Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China | | | ZHU Liang | Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China | |
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| 中文摘要: |
| 摘要 目的：探索AXL在肺腺癌细胞（Lung adenocarcinoma cell, LAC） EGFR-TKIs获得性耐药中的作用，为肺癌临床治疗和新型药物的研发提供实验依据。方法：构建EGFR-TKIs获得性耐药的肺腺癌模型并通过CCK-8法检测耐药株对肺腺癌靶向治疗药物吉非替尼（Gefitinib）、厄洛替尼（Erlotinib）和奥希替尼（Osimertinib）的敏感性。基于基因组学分析筛选出潜在的克服耐药的靶点AXL，通过Western blot和qRT-PCR技术检测AXL的表达情况，并同时检测上皮-间质转化（Epithelial-mesenchymal transition, EMT）分子标志物。R428是AXL的小分子抑制剂，通过CCK-8法、Transwell以及划痕实验等探究靶向AXL对肺腺癌亲本及耐药株增殖和迁移能力的影响。结果： AXL在构建的耐药株中显著高表达，其蛋白表达水平上调15-20倍（P<0.001），mRNA水平上调2-5倍（P<0.01）；EGFR-TKIs耐药株发生上皮间质转化（EMT）;靶向AXL选择性抑制耐药株的增殖能力并且恢复了耐药株对EGFR-TKIs的敏感性（P<0.001）；靶向AXL显著抑制耐药株增强的迁移能力，与亲本株相比最高抑制率可达80%左右（P<0.001）。结论：用遗传学和药理学手段靶向AXL可以显著逆转肺腺癌对EGFR-TKIs耐药，逆转耐药株所增强的迁移等肿瘤生物学特征，对克服EGFR-TKIs获得性耐药有着重要的临床治疗价值以及转化医学前景。 |
| 英文摘要: |
| ABSTRACT Objective: To investigate the role of AXL in the acquired resistance to EGFR-TKIs in lung adenocarcinoma cells, and provide experimental evidence for the clinical treatment of lung cancer and the development of new drugs. Methods: EGFR-TKIs resistant lung adenocarcinoma cell models were derived and subjected to the assays such as CCK-8 assay. Transcriptome sequencing of the cells revealed an upregulated expression of AXL, a gene intrinsically linked to and driving EMT. The upregulation of AXL was confirmed by western blot and qRT-PCR. R428 is an inhibitor of AXL. The effect of cell proliferation and migration were measured by using CCK-8 assay, transwell test and wound-healing assay after targeting AXL. Results: AXL was highly expressed in EGFR-TKIs resistant cells, and the expression level was up-regulated by 15-20 fold (P<0.001), the mRNA level was up-regulated by 2-5 fold (P<0.01); EGFR-TKIs resistant cells acquired epithelial-mesenchymal transition (EMT) properties; Targeting AXL increased the drug susceptibility and attenuated the proliferative capacity of drug-resistant cells; The enhanced migration ability of the resistant cells could be significantly attenuated by targeting AXL, and the highest inhibition rate compared to control can be up to about 80 % (P<0.01). Conclusion: Targeting AXL can significantly reverse the resistance in vitro and the biological characteristics of tumor cells such as the enhanced migration ability of the resistant cells, which has important clinical therapeutic value and prospects to overcome the EGFR-TKIs acquired resistance. |
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