Cigarette smoking impairs the response of EGFR-TKIs therapy in lung adenocarcinoma patients by promoting EGFR signaling and epithelial-mesenchymal transition.
Cigarette smoking impairs the response of EGFR-TKIs therapy in lung adenocarcinoma patients by promoting EGFR signaling and epithelial-mesenchymal transition.
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吸烟通过促进 EGFR 信号传导和上皮间质转化，损害肺腺癌患者 EGFR-TKIs 治疗的反应。
DOI：
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
ming liu;Zhou C;Zheng J
吸烟是非小细胞肺癌（NSCLC）的最高危险因素，越来越多的证据表明吸烟与NSCLC的高复发率和低治疗反应相关。另一方面，表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI），如吉非替尼，已被证明是治疗NSCLC的有效和安全的策略。尽管累积的临床数据表明，吸烟史可能影响EGFR-TKI的治疗效果，即使是在携带敏感EGFR突变的NSCLC患者中，吸烟对NSCLC患者EGFR-TKI治疗疗效的确切影响仍然是排他性的。在本研究中，我们首先通过回顾性分析临床数据，确定吸烟暴露对EGFR-TKI治疗突变阳性肺腺癌患者疗效的不良影响。吸烟患者对治疗的低反应性伴随EGFR下游信号分子ERK 1/2和AKT的持续激活，而吉非替尼不能抑制这种激活，从而导致EGFR-TKI治疗失败。基于我们的体外数据，还发现长期吸烟提取物（CSE）暴露诱导上皮-间充质转化（EMT），这也可能有助于获得性耐药EGFR-TKI。综上所述，我们的研究结果表明，吸烟负调控肺腺癌患者EGFR-TKI治疗的临床结果，这与EGFR信号转导的激活和EMT的诱导相关。
Cigarette smoking represents for the highest risk-factor for non-small cell lung cancer (NSCLC), and a growing body of evidence suggested that smoking was associated with a high recurrence and poor therapeutic response of NSCLC as well. On the other hand, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as gefitinib, has been proved to be an efficient and safe strategy for treating NSCLC. Although accumulating clinical data suggested that smoking history might influence the therapeutic effects of EGFR-TKIs even in NSCLC patients harboring sensitive EGFR mutation, the exact effects of cigarette smoking on the efficacy of EGFR-TKIs treatment in NSCLC patients remain exclusive. In this study, we firstly identified the adverse effect of smoking exposure on the efficacy of EGFR-TKIs treatment against lung adenocarcinoma in mutation-positive patients by retrospective analysis of clinical data. The hypo-responsiveness of smoking patients on the therapy was accompanied with persistent activation of EGFR-downstream signal molecules ERK1/2 and AKT, which could not be inhibited by gefitinib and thus lead to the failure of EGFR-TKIs treatment. Based on our in vitro data, it was also found that long-term cigarette smoking extract (CSE) exposure induced epithelial-mesenchymal transition (EMT), which might also contribute to acquired resistance to EGFR-TKIs. Taken together, our findings suggested that cigarette smoking negatively regulated the clinical outcome of EGFR-TKIs therapy in lung adenocarcinoma patients, which was correlated with the activation of EGFR signaling and the induction of EMT.
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DOI：
10.1136/bmj.b5569
发表时间：
2010-01-21
期刊：
BMJ (Clinical research ed.)
影响因子：
--
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