Fulvestrant increases gefitinib sensitivity in non-small cell lung cancer cells by upregulating let-7c expression.
Fulvestrant increases gefitinib sensitivity in non-small cell lung cancer cells by upregulating let-7c expression.
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DOI：
10.1016/j.biopha.2013.10.007
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发表时间：
2014-04
期刊：
影响因子：
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通讯作者：
H. Shen;Jinyuan Liu;Rongsheng Wang;Xu Qian;Ruitong Xu;Tongpeng Xu;Qi Li;Lin Wang;Zhumei Shi;Jitai Zheng;Qiu-dan Chen;Y. Shu
中科院分区：
文献类型：
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作者：
H. Shen;Jinyuan Liu;Rongsheng Wang;Xu Qian;Ruitong Xu;Tongpeng Xu;Qi Li;Lin Wang;Zhumei Shi;Jitai Zheng;Qiu-dan Chen;Y. Shu
具有活化表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者可从EGFR-酪氨酸激酶抑制剂（EGFR-TKI）（即吉非替尼和厄洛替尼）治疗中获益。然而，这些患者最终会对EGFR-TKI产生耐药性。约50%的这种获得性耐药性可能是EGFR基因中的继发性突变的结果，例如对应于T790 M的突变。在我们之前的研究中，我们发现与单独使用氟维司群或吉非替尼相比，氟维司群和吉非替尼联合治疗可降低H1975 NSCLC细胞的增殖;然而，联合治疗效果改善的分子机制仍然未知。在这项研究中，我们证实了氟维司群增加了H1975细胞对吉非替尼的敏感性，并发现let-7 c在氟维司群处理的细胞中上调最多。我们的数据显示let-7 c通过抑制RAS和失活磷酸肌醇3-激酶（PI 3 K）/AKT和丝裂原激活的细胞外信号调节激酶（MEK）/细胞外信号调节激酶（ERK）信号通路来增加吉非替尼的敏感性。总之，我们的研究结果表明，let-7 c在氟维司群诱导的H1975细胞吉非替尼敏感性上调中起重要作用。
Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), namely, gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. About 50% of this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as the one corresponding to T790M. In our previous study, we found that combined treatment with fulvestrant and gefitinib decreases the proliferation of H1975 NSCLC cells, compared to treatment with either fulvestrant or gefitinib alone; however, the molecular mechanism for the improved effects of the combination treatment are still unknown. In this study, we confirmed that fulvestrant increases the gefitinib sensitivity of H1975 cells and found that let-7c was most upregulated in the fulvestrant-treated cells. Our data revealed that let-7c increases gefitinib sensitivity by repressing RAS and inactivating the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. Taken together, our findings suggest that let-7c plays an important role in fulvestrant-induced upregulation of gefitinib sensitivity in H1975 cells.