Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression
Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression
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DOI：
10.1093/jnci/djw122
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发表时间：
2016-10-01
影响因子：
10.3
通讯作者：
Teicher, Beverly A.
中科院分区：
文献类型：
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作者：
Polley, Eric;Kunkel, Mark;Teicher, Beverly A.
背景：小细胞肺癌(SCLC)是一种侵袭性、顽固性癌症，确诊时常发生转移，复发后化疗无反应，治疗难度大。方法：对63株人小细胞肺癌和3株非小细胞肺癌对103种美国食品和药物管理局批准的肿瘤药物和423种研究药物进行筛选。研究试剂库是一组不同的小分子，其中包括针对同一分子实体的多个化合物。使用ATP Lite终点对这些化合物进行了9种浓度、96小时暴露时间的三重筛选。用外显子阵列检测基因表达，直接数字检测获得microRNA的表达。结果：给出了靶标的抑制物：BCL2、PARP1、mTOR、IGF1R、KSP/EG5、PLK-1、AURK和FGFR1的结果。关系图确定了具有相似反应模式的化合物。无监督的microRNA聚类导致了三个不同的小细胞肺癌亚群。药物反应与microRNA表达的相关性表明，对依托泊苷和拓扑替康最敏感的株系表达高miR-200C-3p，低miR-140-5p和miR-9-5p。BCL-2/BCL-XL抑制剂产生类似的反应模式。对ABT-737的敏感性与较高的ASCL1和BCL2相关。几类靶向调节有丝分裂的核蛋白的化合物产生了与依托泊苷不同的反应模式。结论：靶向核激酶的药物在小细胞肺癌细胞系中似乎是有效的。需要确认异种移植物中的小细胞肺癌株的发现。药物和化合物反应、基因表达和微核糖核酸表达数据可在http://sclccelllines.cancer.gov.上公开获得。
Background: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat.Methods: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103US Food and Drug Administration-approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations.Results: Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug responsewithmicro-RNA expression indicated that lines most sensitive to etoposide and topotecan expressed highmiR-200c-3p and lowmiR-140-5p andmiR-9-5p. The BCL-2/BCL-XL inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulatingmitosis produced a response pattern distinct from the etoposide response pattern.Conclusions: Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sclccelllines.cancer.gov.