Up-regulation of the Hippo pathway effector TAZ renders lung adenocarcinoma cells harboring EGFR-T790M mutation resistant to gefitinib.
Up-regulation of the Hippo pathway effector TAZ renders lung adenocarcinoma cells harboring EGFR-T790M mutation resistant to gefitinib.
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Hippo通路效应子TAZ的上调使携带EGFR-T790M突变的肺腺癌细胞对吉非替尼产生耐药性
DOI：
10.1186/2045-3701-5-7
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发表时间：
2015
影响因子：
7.5
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Xu W;Wei Y;Wu S;Wang Y;Wang Z;Sun Y;Cheng SY;Wu J
研究背景上皮生长因子受体（EGFR）T790 M突变是肺癌患者对EGFR酪氨酸激酶抑制剂（EGFR-TKI）治疗产生获得性耐药的主要原因。海马通路效应，TAZ，已成为一个关键的球员在器官生长和肿瘤发生，包括lung cancer.ResultsIn这项研究中，我们发现高TAZ表达的非小细胞肺癌（NSCLC）细胞窝藏双重突变和TAZ耗尽敏化他们的反应EGFR-TKI。从机制上讲，T790 M诱导的耐药细胞中TAZ的敲低导致体外非锚定依赖性生长、体内肿瘤形成和对吉非替尼的耐药性减少，与上皮-间质转化（EMT）相关，并抑制迁移和侵袭。此外，我们证实CTGF和AXL，新的EMT标记物和潜在的治疗目标，克服EGFR抑制剂耐药，作为直接的转录靶点TAZ. ConclusionsTogether，这项研究表明，表达TAZ是一个内在的机制T790 M诱导的耐药EGFR-TKI。联合靶向EGFR和TAZ可增强EGFR-TKI在NSCLC获得性耐药中的疗效。
BackgroundThe T790M mutation of epithelial growth factor receptor (EGFR) is a major cause of the acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKIs) treatment for lung cancer patients. The Hippo pathway effector, TAZ, has emerged as a key player in organ growth and tumorigenesis, including lung cancer.ResultsIn this study, we have discovered high TAZ expression in non-small cell lung cancer (NSCLC) cells harboring dual mutation and TAZ depletion sensitized their response to EGFR-TKIs. Mechanistically, knockdown of TAZ in T790M-induced resistant cells leaded to reduced anchorage-independent growthin vitro, tumor formation and resistance to gefitinibin vivo, correlated with epithelial-mesenchymal transition (EMT) and suppressed migration and invasion. Furthermore, we confirmed CTGF and AXL, novel EMT markers and potential therapeutic targets for overcoming EGFR inhibitor resistance, as directly transcriptional targets of TAZ.ConclusionsTaken together, this study suggests that expression of TAZ is an intrinsic mechanism of T790M-induced resistance in response to EGFR-TKIs. Combinational targeting on both EGFR and TAZ may enhance the efficacy of EGFR-TKIs in acquired resistance of NSCLC.
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