Continuous exposure of non-small cell lung cancer cells with wild-type EGFR to an inhibitor of EGFR tyrosine kinase induces chemoresistance by activating STAT3
Continuous exposure of non-small cell lung cancer cells with wild-type EGFR to an inhibitor of EGFR tyrosine kinase induces chemoresistance by activating STAT3
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将具有野生型 EGFR 的非小细胞肺癌细胞持续暴露于 EGFR 酪氨酸激酶抑制剂，可通过激活 STAT3 诱导化疗耐药。
DOI：
10.3892/ijo.2015.2898
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发表时间：
2015-05-01
影响因子：
5.2
通讯作者：
Wang, Yongsheng
中科院分区：
文献类型：
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作者：
Tang, Jie;Guo, Fuchun;Wang, Yongsheng
表皮生长因子受体酪氨酸激酶抑制剂（EGFR- tkis）已显示出抑制含有EGFR突变（EGFR-mts）的非小细胞肺癌（NSCLC）细胞生长的良好效果。然而，许多接受EGFR- tki治疗后化疗的NSCLC患者具有未知的EGFR状态，包括野生型EGFR （EGFR-wt）。对于化疗前EGFR-TKI治疗的潜在影响知之甚少。我们研究了EGFR-TKIs连续暴露4周对EGFR-wt NSCLC H1299的影响和潜在的分子事件。这种治疗方法显著提高了几种相关化疗药物的IC50：顺铂(DDP)(29.25 + / - 6.1μM为吉非替尼,埃罗替尼43.25 + / - 14.87μM,和6.92 + / - 1.15μM的父母),紫杉醇(11.16 + / - 3.36μM为吉非替尼,埃罗替尼9.16 + / - 1.41μM,和2.09 + / - 0.44μM的父母),吉西他滨(47.18 + / - 6.2μM为吉非替尼,40.36 - 11.1 yM埃罗替尼,和16.00 + / - 3.38μM父母)和培美曲塞(11.78 + / - 4.07μM为吉非替尼,埃罗替尼15.97 + / - 7.23μM,和4.72 + / - 1.9μM的父母)。这种化学耐药严重依赖于中介信号换能器和转录激活因子3 （STAT3）的激活。在暴露于EGFR- tkis 4周的细胞中，发现STAT3的激活与EGFR无关，并且独立于IL-6和-22。STAT3抑制剂NSC 74859治疗能够逆转TKI暴露诱导的EGFR-wt NSCLC细胞的化疗耐药。在携带EGFR L858R和T790M突变的H1975细胞中也观察到类似的现象。基于EGFR-wt NSCLC细胞系长期暴露于EGFR-TKI后观察到的分子事件，本研究表明，对于可以接受化疗的EGFR-wt患者，不应推荐使用此类药物。该研究还表明，STAT3抑制剂可能有助于治疗由于获得性T790M突变而表现出EGFR-TKI耐药的NSCLC患者。
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown promising effects against the growth of non-small cell lung cancer (NSCLC) cells harboring EGFR mutations (EGFR-mts). However, many patients with NSCLC that are accepted for EGFR-TKI treatment followed by chemotherapy possess an unknown EGFR status including wild-type EGFR (EGFR-wt). Little is known ab6ut the potential effects of EGFR-TKI treatment prior to chemotherapy. We investigated the effects and underlying molecular events of 4 weeks of continuous exposure to EGFR-TKIs in the EGFR-wt NSCLC line H1299. This treatment dramatically increased the IC50 of several relevant chemotherapeutic agents: cisplatin (DDP) (29.25 +/- 6.1 mu M for gefitinib, 43.25 +/- 14.87 mu M for erlotinib, and 6.92 +/- 1.15 mu M for parental), paclitaxel (11.16 +/- 3.36 mu M for gefitinib, 9.16 +/- 1.41 mu M for erlotinib, and 2.09 +/- 0.44 mu M for parental), gemcitabine (47.18 +/- 6.2 mu M for gefitinib, 40.36 11.1 yM for erlotinib, and 16.00 +/- 3.38 mu M for parental) and pemetrexed (11.78 +/- 4.07 mu M for gefitinib, 15.97 +/- 7.23 mu M for erlotinib, and 4.72 +/- 1.9 mu M for parental). This chemoresistance was critically dependent on the activation of the mediator signal transducer and activator of transcription 3 (STAT3). In cells exposed to EGFR-TKIs for 4 weeks, activation of STAT3 was found to be unrelated to EGFR and to be independent of IL-6 and -22. Treatment with the STAT3 inhibitor NSC 74859 was able to reverse the TKI exposure-induced chemoresistance in EGFR-wt NSCLC cells. Similar phenomena were observed in H1975 cells harboring EGFR L858R and T790M mutations. Based on the observed molecular events following long exposure of an EGFR-wt NSCLC cell line to an EGFR-TKI, this study indicates that such drugs should be not recommended for EGFR-wt patients who can undergo chemotherapy. This study also suggests that STAT3 inhibitors may aid in the treatment NSCLC patients who exhibit EGFR-TKI resistance due to an acquired T790M mutation.