Zhang Fu-quan, Yang Wen-tao, Duan Shan-zhou, Xia Ying-chen, Zhu Rong-ying, Chen Yong-bing
Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Oncotarget. 2015 Jun 10;6(16):14329-43. doi: 10.18632/oncotarget.3685.
Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, NSCLC patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of TG101348 (a JAK2 inhibitor) on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation, apoptosis, gene expression and tumor growth were evaluated by diphenyltetrazolium bromide (MTT) assay, flow cytometry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, Western Blot and a xenograft mouse model, respectively. Results showed that erlotinib had a stronger impact on the induction of apoptosis in erlotinib-sensitive PC-9 cells but had a weaker effect on erlotinib-resistant H1975 and H1650 cells than TG101348. TG101348 significantly enhanced the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, stimulated erlotinib-induced apoptosis and downregulated the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of TG101348 and erlotinib induced apoptosis, inhibited the activation of p-EGFR and p-STAT3, and inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that TG101348 is a potential adjuvant for NSCLC patients during erlotinib treatment.
具有表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者对EGFR酪氨酸激酶抑制剂（EGFR-TKI）敏感。然而，具有继发性体细胞EGFR突变的NSCLC患者对EGFR-TKI治疗耐药。在本研究中，我们调查了TG101348（一种JAK2抑制剂）对厄洛替尼耐药的NSCLC细胞肿瘤生长的影响。分别通过溴化四氮唑蓝（MTT）法、流式细胞术、末端脱氧核苷酸转移酶生物素-dUTP缺口末端标记（TUNEL）染色、蛋白质免疫印迹法和异种移植小鼠模型评估细胞增殖、凋亡、基因表达和肿瘤生长。结果显示，与TG101348相比，厄洛替尼对厄洛替尼敏感的PC-9细胞凋亡诱导作用更强，但对厄洛替尼耐药的H1975和H1650细胞的作用较弱。TG101348显著增强了厄洛替尼对厄洛替尼耐药NSCLC细胞的细胞毒性，刺激了厄洛替尼诱导的凋亡，并下调了厄洛替尼耐药NSCLC细胞中EGFR、p-EGFR、p-STAT3、Bcl-xL和survivin的表达。此外，TG101348与厄洛替尼联合治疗可诱导凋亡，抑制p-EGFR和p-STAT3的激活，并在体内抑制厄洛替尼耐药NSCLC细胞的肿瘤生长。我们的结果表明，TG101348是NSCLC患者在厄洛替尼治疗期间的一种潜在佐剂。
