Epithelial-Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor-Mediated Apoptosis in Non-Small Cell Lung Cancer.
Epithelial-Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor-Mediated Apoptosis in Non-Small Cell Lung Cancer.
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DOI：
10.1158/1078-0432.ccr-14-2890
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Johnson FM
中科院分区：
文献类型：
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作者：
Ferrarotto R;Goonatilake R;Yoo SY;Tong P;Giri U;Peng S;Minna J;Girard L;Wang Y;Wang L;Li L;Diao L;Peng DH;Gibbons DL;Glisson BS;Heymach JV;Wang J;Byers LA;Johnson FM
为了确定非小细胞肺癌（NSCLC）的新治疗靶点，我们系统地检索了2个癌细胞系数据库，以获取广泛药物的敏感性数据。我们确定polo样激酶1 （PLK1）是最有希望进一步研究的靶点，基于一组敏感的非小细胞肺癌细胞系和处于晚期临床开发的抑制剂。为了确定非小细胞肺癌对PLK1抑制反应的潜在生物标志物和PLK1抑制剂诱导细胞凋亡的机制，使用3种PLK1抑制剂（volasertib、BI2536和GSK461364）对非小细胞肺癌细胞系进行了基因和蛋白表达、基因突变和药物敏感性的综合分析。NSCLC细胞系对PLK1抑制具有不同的敏感性，少数细胞系对所有3种抑制剂均表现出敏感性。PLK1抑制导致G2/M阻滞，但只有对治疗敏感的细胞系在PLK1抑制后发生大量凋亡。具有高上皮-间充质转化基因特征评分的NSCLC细胞系（间充质细胞系）对PLK1抑制的敏感性高于上皮细胞系（P < 0.02）。同样，蛋白质组学分析表明，E-cadherin在耐药细胞株中的表达高于敏感细胞株（P < 0.01）。通过表达microRNA miR-200诱导上皮表型增加了细胞对PLK1抑制的抗性。此外，KRAS突变和紧密连接、ErbB和Rho信号通路的改变与NSCLC的药物反应相关。在这篇首次报道的PLK1抑制剂敏感性的大规模综合分析中，我们证明了上皮-间质转化导致非小细胞肺癌细胞PLK1抑制敏感性。我们的发现对间充质非小细胞肺癌具有重要的临床意义，间充质非小细胞肺癌是一种重要的疾病亚型，与目前批准的靶向治疗耐药有关。
To identify new therapeutic targets for non-small cell lung cancer (NSCLC), we systematically searched 2 cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development. To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor-induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using 3 PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines. The NSCLC cell lines had different sensitivities to PLK1 inhibition, with a minority demonstrating sensitivity to all 3 inhibitors. PLK1 inhibition led to G2/M arrest, but only treatment-sensitive cell lines underwent substantial apoptosis following PLK1 inhibition. NSCLC lines with high epithelial-mesenchymal transition gene signature scores (mesenchymal cell lines) were more sensitive to PLK1 inhibition than were epithelial lines (P < 0.02). Likewise, proteomic profiling demonstrated that E-cadherin expression was higher in the resistant cell lines than in the sensitive ones (P < 0.01). Induction of an epithelial phenotype by expression of the microRNA miR-200 increased cellular resistance to PLK1 inhibition. Also, KRAS mutation and alterations in the tight-junction, ErbB, and Rho signaling pathways correlated with drug response of NSCLC. In this first reported large-scale integrated analysis of PLK1 inhibitor sensitivity, we demonstrated that epithelial-mesenchymal transition leads to PLK1 inhibition sensitivity of NSCLC cells. Our findings have important clinical implications for mesenchymal NSCLC, a significant subtype of the disease that is associated with resistance to currently approved targeted therapies.