Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells.
Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells.
复制标题
获得的对EGFR抑制剂的耐药性与癌细胞中干细胞样性质的表现有关。
DOI：
10.1158/0008-5472.can-12-4136
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发表时间：
2013-05-15
期刊：
影响因子：
11.2
通讯作者：
Miyoshi S
中科院分区：
文献类型：
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作者：
Shien K;Toyooka S;Yamamoto H;Soh J;Jida M;Thu KL;Hashida S;Maki Y;Ichihara E;Asano H;Tsukuda K;Takigawa N;Kiura K;Gazdar AF;Lam WL;Miyoshi S
对表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)的获得性耐药是肺癌治疗中的一个关键问题。尽管有几种机制被证明对获得性耐药负有责任，但尚未发现所有机制。在这项研究中，我们研究了在EGFR突变肺癌中获得的对EGFR-TKI耐药细胞的分子和细胞学特征。采用逐步递增和高浓度暴露的方法，建立了4株EGFR突变细胞株对吉非替尼的耐药亚系。对这些抗性亚系的分子图谱和细胞表型进行了鉴定。虽然先前报道了包括继发性EGFR T790M突变、MET扩增和出现上皮向间充质转化(EMT)特征在内的变化，但这两种药物暴露方法显示出不同的耐药机制。具有EMT特征的耐药细胞表现出DNA甲基化下调miRNA-200C的表达。此外，经高浓度暴露的HCC827亚系不仅表现出EMT特征，而且具有干细胞样特性，包括乙醛脱氢酶异构体1(ALDH1A1)的高表达、侧群增加和自我更新能力。与亲本细胞相比，具有干细胞样特性的耐药亚系对传统化疗药物具有耐药性，但对组蛋白脱乙酰酶和蛋白酶体抑制剂同样敏感。ALDH1A1在对吉非替尼具有获得性耐药的临床样本中上调。综上所述，我们的研究表明，EGFR-TKI暴露的方式影响了EGFR-TKI治疗的获得性耐药机制和干细胞样属性的出现。
Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell–like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell–like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell–like property with EGFR-TKI treatment.