Department of Biochemistry and Molecular Biology, Shandong University School of Basic Medical Sciences, Jinan, China.
Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China.
Mol Oncol. 2018 Jun;12(6):883-895. doi: 10.1002/1878-0261.12200. Epub 2018 May 9.
Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is an effective treatment for non-small-cell lung cancer (NSCLC) with EGFR activating mutations, but inevitably, the clinical efficacy is impeded by the emergence of acquired resistance. The tumor suppressor gene FBXW7 modulates chemosensitivity in various human cancers. However, its role in EGFR-TKI therapy in NSCLC has not been well studied. Here, we demonstrate that the mice with deficient Fbxw7 have greater susceptibility to urethane-induced lung tumor development. Through analysis of The Cancer Genome Atlas data, we show that deletion of FBXW7 occurs in 30.9% of lung adenocarcinomas and 63.5% of lung squamous cell carcinomas, which significantly leads to decrease in FBXW7 mRNA expression. The reduction in FBXW7 mRNA level is associated with poor overall survival in lung cancer patients. FBXW7 knockdown dramatically promotes epithelial-mesenchymal transition, migration, and invasion in NSCLC cells. Moreover, with silenced FBXW7, EGFR-TKI-sensitive cells become resistant to gefitinib, which is reversed by the mammalian target of rapamycin inhibitor, rapamycin. Furthermore, xenograft mouse model studies show that FBXW7 knockdown enhances tumorigenesis and resistance to gefitinib. Combination of gefitinib with rapamycin treatment suppresses tumor formation of gefitinib-resistant (GR) FBXW7-knockdown cells. In conclusion, our findings suggest that loss of FBXW7 promotes NSCLC progression as well as gefitinib resistance and combination of gefitinib and rapamycin may provide an effective therapy for GR NSCLC.
吉非替尼是一种表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），是治疗具有 EGFR 激活突变的非小细胞肺癌（NSCLC）的有效药物，但不可避免的是，临床疗效受到获得性耐药的阻碍。肿瘤抑制基因 FBXW7 调节各种人类癌症的化疗敏感性。然而，它在 NSCLC 中 EGFR-TKI 治疗中的作用尚未得到很好的研究。在这里，我们证明 Fbxw7 缺失的小鼠对尿嘧啶诱导的肺肿瘤发展具有更高的易感性。通过对癌症基因组图谱数据的分析，我们表明 FBXW7 的缺失发生在 30.9%的肺腺癌和 63.5%的肺鳞癌中，这显著导致 FBXW7 mRNA 表达降低。FBXW7 mRNA 水平的降低与肺癌患者的总生存率降低相关。FBXW7 敲低显著促进 NSCLC 细胞的上皮-间充质转化、迁移和侵袭。此外，沉默 FBXW7 后，EGFR-TKI 敏感细胞对吉非替尼产生耐药性，而雷帕霉素（mammalian target of rapamycin inhibitor，mTOR 抑制剂）可逆转这一现象。此外，异种移植小鼠模型研究表明，FBXW7 敲低增强了肿瘤发生和对吉非替尼的耐药性。吉非替尼与雷帕霉素联合治疗可抑制 FBXW7 敲低的 gefitinib 耐药细胞的肿瘤形成。总之，我们的研究结果表明，FBXW7 的缺失促进了 NSCLC 的进展以及吉非替尼的耐药性，吉非替尼与雷帕霉素的联合治疗可能为 gefitinib 耐药 NSCLC 提供有效的治疗策略。
