Reverse epithelial-mesenchymal transition contributes to the regain of drug sensitivity in tyrosine kinase inhibitor-resistant non-small cell lung cancer cells.
Reverse epithelial-mesenchymal transition contributes to the regain of drug sensitivity in tyrosine kinase inhibitor-resistant non-small cell lung cancer cells.
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DOI：
10.1371/journal.pone.0180383
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Liu YP
中科院分区：
文献类型：
--
作者：
Lee AF;Chen MC;Chen CJ;Yang CJ;Huang MS;Liu YP
酪氨酸激酶抑制剂（TKI）目前是表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者的一线治疗药物。这些患者在对TKI产生耐药性后接受含铂化疗作为二线治疗。许多患者在化疗失败后重新对一线治疗中使用的TKI敏感。然而，TKI敏感性恢复的分子机制在很大程度上是未知的。在这项研究中，我们建立了吉非替尼耐药的PC9和HCC 827细胞系，它们没有携带EGFR T790M突变和MET扩增，但表现出上皮间质转化（EMT）表型。EMT诱导剂Snail或Slug在亲本系中的过表达促进了它们对吉非替尼的抗性。吉非替尼耐药细胞系在无吉非替尼的培养基中长期培养后恢复了对吉非替尼的敏感性，并显示出逆转的EMT表型。通过稳定表达Snail或Slug阻断反向EMT可防止TKI敏感性的恢复。总之，逆转EMT是TKI耐药NSCLC细胞恢复TKI敏感性的主要机制之一，表明靶向EMT过程的小分子的开发可能延长TKI在EGFR突变NSCLC患者中的疗效。
Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.
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影响因子：
17.1
作者：
Chmielecki J;Foo J;Oxnard GR;Hutchinson K;Ohashi K;Somwar R;Wang L;Amato KR;Arcila M;Sos ML;Socci ND;Viale A;de Stanchina E;Ginsberg MS;Thomas RK;Kris MG;Inoue A;Ladanyi M;Miller VA;Michor F;Pao W
通讯作者：
Pao W
影响因子：
3.7
作者：
Pallier K;Cessot A;Côté JF;Just PA;Cazes A;Fabre E;Danel C;Riquet M;Devouassoux-Shisheboran M;Ansieau S;Puisieux A;Laurent-Puig P;Blons H
通讯作者：
Blons H
影响因子：
3.8
作者：
Haslehurst AM;Koti M;Dharsee M;Nuin P;Evans K;Geraci J;Childs T;Chen J;Li J;Weberpals J;Davey S;Squire J;Park PC;Feilotter H
通讯作者：
Feilotter H
DOI：
10.1164/rccm.201412-2226oc
发表时间：
2016-04-15
影响因子：
24.7
作者：
Hsu, Che-Yu;Lin, Cheng-Han;Lu, Pei-Jung
通讯作者：
Lu, Pei-Jung
影响因子：
11.2
作者：
Ogino, Atsuko;Kitao, Hiroyuki;Tanimoto, Mitsune
通讯作者：
Tanimoto, Mitsune