Tyrosine kinase inhibitor‐induced IL‐6/STAT3 activation decreases sensitivity of EGFR‐mutant non‐small cell lung cancer to icotinib

Wang Jinyao; Wang Yizhe; Zheng Chunlei; Hou Kezuo; Zhang Tieqiong; Qu Xiujuan; Liu Yunpeng; Kang Jian; Hu Xuejun; Che Xiaofang

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Tyrosine kinase inhibitor‐induced IL‐6/STAT3 activation decreases sensitivity of EGFR‐mutant non‐small cell lung cancer to icotinib

机译：酪氨酸激酶抑制剂诱导的IL-6 / Stat3活化会降低EGFR-突变体非小细胞肺癌对icotinib的敏感性

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Abstract Tyrosine kinase Inhibitors (TKIs) of epidermal growth factor receptor (EGFR) has considerably benefited for non‐small cell lung carcinomas (NSCLC) harbor mutations in EGFR. However, the factors attenuating EGFR‐TKI efficiency are obstacles to inhibit the proliferation of EGFR‐mutant NSCLC cells successfully. Clarifying the insensitivity mechanisms of EGFR‐TKI would help to develop new treatment strategy. In this study, the sensitivity of EGFR‐mutant NSCLC cell lines, PC9 and HCC827, to icotinib was detected. Similar with other EGFR‐TKIs such as gefitinib and erlortinib in previous research, the proliferation of two cell lines was apparently inhibited. However, we surprisingly found that contrast with the suppression of EGFR‐AKT/ERK pathway, STAT3 was significantly activated in PC9 cells with the treatment of icotinib, but not in HCC827 cells. Further study confirmed that icotinib concomitantly induced IL‐6 secretion and src activation in PC9 cells. Moreover, with the treatment of IL‐6 neutralizing antibody or src inhibitor, dasatinib, icotinib‐induced phosphorylation of STAT3 was reduced, as well as the sensitivity of PC9 to icotinib was also partially increased. Our results suggest that Src/IL‐6/STAT3 bypass pathway is activated to maintain cell survival when the EGFR pathway was inhibited by TKIs, even in some EGFR‐mutant NSCLC cells sensitive to TKIs. This finding provides a groundwork for potential combinatorial treatment with TKIs and Src or STAT3 inhibitor to improve icotinib sensitivity.

机译：摘要表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂（TKIs）对EGFR突变的非小细胞肺癌（NSCLC）具有显著的治疗作用。然而，降低EGFR-TKI效率的因素是成功抑制EGFR突变NSCLC细胞增殖的障碍。阐明EGFR-TKI的不敏感机制将有助于开发新的治疗策略。本研究检测了EGFR突变的NSCLC细胞系PC9和HCC827对伊可替尼的敏感性。与之前研究中的其他EGFR-TKI（如吉非替尼和厄洛替尼）类似，两种细胞系的增殖明显受到抑制。然而，我们惊讶地发现，与EGFR-AKT/ERK途径的抑制相比，在伊可替尼治疗的PC9细胞中，STAT3被显著激活，而在HCC827细胞中则没有。进一步研究证实，伊可替尼同时诱导PC9细胞分泌IL-6和src活化。此外，通过IL-6中和抗体或src抑制剂达沙替尼的治疗，伊可替尼诱导的STAT3磷酸化降低，PC9对伊可替尼的敏感性也部分增加。我们的结果表明，当EGFR通路被TKIs抑制时，Src/IL-6/STAT3旁路通路被激活以维持细胞存活，即使在一些对TKIs敏感的EGFR突变NSCLC细胞中也是如此。这一发现为TKIs和Src或STAT3抑制剂的潜在组合治疗提供了基础，以提高伊可替尼的敏感性。

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来源
《Cell biology international.》 |2018年第10期|共8页
作者
Wang Jinyao; Wang Yizhe; Zheng Chunlei; Hou Kezuo; Zhang Tieqiong; Qu Xiujuan; Liu Yunpeng; Kang Jian; Hu Xuejun; Che Xiaofang;
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作者单位

Department of Respiratory and Infectious Disease of GeriatricsThe First Hospital of China Medical;

Department of Respiratory and Infectious Disease of GeriatricsThe First Hospital of China Medical;

Department of Medical OncologyKey Laboratory of Anticancer Drugs and Biotherapy of Liaoning;

Department of Medical OncologyKey Laboratory of Anticancer Drugs and Biotherapy of Liaoning;

Department of Respiratory and Infectious Disease of GeriatricsThe First Hospital of China Medical;

Department of Medical OncologyKey Laboratory of Anticancer Drugs and Biotherapy of Liaoning;

Department of Medical OncologyKey Laboratory of Anticancer Drugs and Biotherapy of Liaoning;

Department of Pulmonary MedicineThe First Hospital of China Medical UniversityNo. 155 North;

Department of Respiratory and Infectious Disease of GeriatricsThe First Hospital of China Medical;

Department of Medical OncologyKey Laboratory of Anticancer Drugs and Biotherapy of Liaoning;

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原文格式 PDF
正文语种 eng
中图分类细胞生物学;
关键词
cancer; cytokines/interleukins; EGFR‐TKIs; NSCLC; secretion; STAT3;

机译：癌症;细胞因子/白细胞介素;EGFR-TKIS;NSCLC;分泌;STAT3;

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专利

1. EGFR tyrosine kinase inhibitor HS-10182 increases radiation sensitivity in non-small cell lung cancers with EGFR T790M mutation [J] . Yang Chen, Youyou Wang, Lujun Zhao, 癌症生物学与医学：英文版 . 2018,第001期
2. EGFR tyrosine kinase inhibitor HS-10182 increases radiation sensitivity in non-small cell lung cancers with EGFR T790M mutation [J] . Yang Chen, Youyou Wang, Lujun Zhao, 癌症生物学与医学（英文版） . 2018,第001期
3. EGFR tyrosine kinase inhibitor HS-10182 increases radiation sensitivity in non-small cell lung cancers with EGFR T790M mutation [J] . Yang Chen, Youyou Wang, Lujun Zhao, 癌症生物学与医学：英文版 . 2018,第001期
4. Phase I trial of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in Chinese patients with non-small cell lung cancer [J] . WANG Hart-ping, ZHANG Li, WANG Yin-xiang, 中华医学杂志：英文版 . 2011,第013期
5. Phase Ⅰ trial of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in Chinese patients with non-small cell lung cancer [J] . WANG Han-ping, XIAO Yi, ZHANG Li, 中华医学杂志（英文版） . 2011,第013期
6. Tyrosine kinase inhibitor‐induced IL‐6/STAT3 activation decreases sensitivity of EGFR‐mutant non‐small cell lung cancer to icotinib [J] . Wang Jinyao, Wang Yizhe, Zheng Chunlei, Cell biology international. . 2018,第10期

机译：酪氨酸激酶抑制剂诱导的IL-6 / Stat3活化降低了EGFR-突变体非小细胞肺癌对icotinib的敏感性
7. 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 [J] . Jie Tang, Fuchun Guo, Yang Du, International journal of oncology . 2015,第5期

机译：将具有野生型EGFR的非小细胞肺癌细胞连续暴露于EGFR酪氨酸激酶抑制剂可通过激活STAT3诱导化学耐药性
8. Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line [J] . Yoshinori Tsukumo, Mikihiko Naito, Takayoshi Suzuki PLoS One . 2020,第3期

机译：EGFR激活突变对克拉斯突变体非小细胞肺癌细胞系酪氨酸激酶抑制剂敏感性的影响
9. Association between tumor heterogeneity and progression-free survival in non-small cell lung cancer patients with EGFR mutations undergoing tyrosine kinase inhibitors therapy [C] . Jiangdian Song, Di Dong, Yanqi Huang, Annual International Conference of the IEEE Engineering in Medicine and Biology Society . 2016

机译：接受酪氨酸激酶抑制剂治疗的EGFR突变非小细胞肺癌患者肿瘤异质性与无进展生存的关系
10. EGFR in Early Non-Small Cell Lung Cancer: Tyrosine Kinase Inhibition in a Neoadjuvant Trial. [D] . Lara-Guerra, Humberto. 2011

机译：早期非小细胞肺癌中的EGFR：新辅助试验中酪氨酸激酶抑制作用。
11. Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line [O] . Yoshinori Tsukumo, Mikihiko Naito, Takayoshi Suzuki 2020

机译：EGFR激活突变对克拉斯突变体非小细胞肺癌细胞系酪氨酸激酶抑制剂敏感性的影响
12. Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells. [O] . Keisuke Tabara, Rina Kanda, Kahori Sonoda, 2012

机译：激活EGFR突变基因的丧失有助于肺癌细胞中对EGFR酪氨酸激酶抑制剂的获得性抗性。
13. Systematic Reviews on Selected Pharmacogenetic Tests for Cancer Treatment: CYP2D6 for Tamoxifen in Breast Cancer, KRAS for anti-EGFR antibodies in Colorectal Cancer, and BCR-ABL1 for Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia. Technology Assessment Report [R] . Terasawa, T., Dahabreh, I., Castaldi, P. J., 2010

机译：针对癌症治疗的选定药物遗传学测试的系统评价：CYp2D6用于乳腺癌中的他莫昔芬，KRas用于结肠直肠癌中的抗EGFR抗体，以及BCR-aBL1用于慢性髓性白血病中的酪氨酸激酶抑制剂。技术评估报告

Tyrosine kinase inhibitor‐induced IL‐6/STAT3 activation decreases sensitivity of EGFR‐mutant non‐small cell lung cancer to icotinib

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