埃克替尼通过p38-MAPK信号通路对涎腺腺样囊性癌ACC-M细胞的凋亡诱导作用

目的：探讨埃克替尼对人涎腺腺样囊性癌细胞ACC-M凋亡的影响,阐明埃克替尼对涎腺腺样囊性癌的治疗作用机制。方法：ACC-M细胞随机分为对照组,2、4、8 μmo1/L^-1埃克替尼组,促分裂原活化蛋白激酶（APK）抑制剂SB203580(20 μmol/L^-1)组,SB203580(20 μmol/L^-1 )+埃克替尼(4 μmol/L^-1 )组。4 h后收
集细胞,采用MTT法检测各组ACC-M细胞的生长抑制率,用caspase-3活力检测试剂盒检测ACC-M细胞的凋亡情况（ 即caspase-3活力）,采用
Westernblotting法检测p-p38-MAPK蛋白的表达水平。结果：与对照组比较,埃克替尼组ACC-M细胞生长抑制率明显升高(P<0.05),caspase-3活力显著增强（P<0.05）,
p-p38-MAPK蛋白表达水平增加（P<0.05）。与4 μmol/L^-1 埃克替尼组比较,SB203580+埃克替尼组p-p38-MAPK蛋白表达水平明显降低（P<0.05）,caspase-3活力显著降低（P<0.05）。结论：埃克替尼可通过上调p-p38-MAPK信号的表达诱导ACC-M细胞凋亡。     

Integrin α5 promotes migration and invasion through the FAK/STAT3/AKT signaling pathway in icotinib-resistant non-small cell lung cancer cells

Patients with non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs) ultimately develop drug resistance and metastasis. Therefore, there is a need to identify the underlying mechanisms of resistance to EGFR-TKIs. In the present study, colony formation and MTT assays were performed to investigate cell viability following treatment with icotinib. Gene Expression Omnibus datasets were used to identify genes associated with resistance. Wound healing and Transwell assays were used to detect cell migration and invasion with icotinib treatment and integrin α5-knockdown. The expression levels of integrin α5 and downstream genes were detected using western blotting. Stable icotinib-resistant (IcoR) cell lines (827/IcoR and PC9/IcoR) were established that showed enhanced malignant properties compared with parental cells (HCC827 and PC9). Furthermore, the resistant cell lines were resistant to icotinib in terms of proliferation, migration and invasion. The enrichment of function and signaling pathways analysis showed that integrin α5-upregulation was associated with the development of icotinib resistance. The knockdown of integrin α5 attenuated the migration and invasion capability of the resistant cells. Moreover, a combination of icotinib and integrin α5 siRNA significantly inhibited migration and partly restored icotinib sensitivity in IcoR cells. The expression levels of phosphorylated (p)-focal adhesion kinase (FAK), p-STAT3 and p-AKT decreased after knockdown of integrin α5, suggesting that FAK/STAT3/AKT signaling had a notable effect on the resistant cells. The present study revealed that the integrin α5/FAK/STAT3/AKT signaling pathway promoted icotinib resistance and malignancy in IcoR NSCLC cells. This signaling pathway may provide promising targets against acquired resistance to EGFR-TKI in patients with NSCLC.     

埃克替尼在伴有 EGFR 敏感突变Ⅱ~ⅢA期非小细胞肺癌术后辅助治疗的应用

1文献来源He J,Su C,Liang W,et al.Icotinib versus chemotherapy as adjuvant treatment for stageⅡ-ⅢA EGFR-mutant non-small-cell lung cancer(EVIDENCE):A randomised,open-label,phase 3 trial[J].Lancet Respir Med,2021,9(9):1021-1029.2证据水平1a。3背景以铂类为基础的辅助化疗是Ⅱ~ⅢA期非小细胞肺癌(non-small-cell lung cancer,NSCLC)患者的标准治疗方案。