Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy.
Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy.
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DOI：
10.1158/1541-7786.mcr-15-0321
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Meyerson M
中科院分区：
文献类型：
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作者：
Gannon HS;Kaplan N;Tsherniak A;Vazquez F;Weir BA;Hahn WC;Meyerson M
体细胞遗传改变的鉴定赋予药物抑制剂的敏感性，导致了新的癌症治疗。为了鉴定赋予异常依赖性的突变，从许多细胞系的数据集中分析了基于shRNA的功能丧失数据，以揭示在一小部分癌细胞系中必不可少的基因。一旦确定了这些细胞系，就利用这些细胞系的详细基因组表征来确定导致这种极端依赖性的基因组畸变。该方法，在一个大的肺癌细胞系的子集，产生了一个单一的肺腺癌细胞系，NCI-H1437，这是敏感的RNA干扰MAP 2K 1的表达。值得注意的是，NCI-H1437是数据集中唯一一个在MAP 2K 1（Q56 P）中具有已知激活突变的肺系。随后使用shRNA和CRISPR-Cas9的验证证实了MAP 2K 1依赖性。体外和体内抑制剂研究证实，NCI-H1437细胞对MEK 1抑制剂敏感，包括FDA批准的药物曲美替尼。与NCI-H1437细胞一样，MAP 2K 1突变体细胞系SNU-C1（结肠）和OCUM-1（胃）在通过Cas9介导的基因编辑消耗MAP 2K 1后显示出活力降低。类似地，与对照细胞系相比，这些细胞系对曲美替尼处理特别敏感。基于这些数据，在MAP 2K 1中携带驱动突变的癌症应该受益于MEK 1抑制剂的治疗。此外，这种功能数据挖掘方法提供了一种通用的方法来实验性地测试赋予肿瘤依赖性的基因组特征。
The identification of somatic genetic alterations that confer sensitivity to pharmacologic inhibitors has led to new cancer therapies. To identify mutations that confer an exceptional dependency, shRNA-based loss-of-function data were analyzed from a dataset of numerous cell lines to reveal genes that are essential in a small subset of cancer cell lines. Once these cell lines were determined, detailed genomic characterization from these cell lines was utilized to ascertain the genomic aberrations that led to this extreme dependency. This method, in a large subset of lung cancer cell lines, yielded a single lung adenocarcinoma cell line, NCI-H1437, which is sensitive to RNA interference of MAP2K1 expression. Notably, NCI-H1437 is the only lung line included in the dataset with a known activating mutation in MAP2K1 (Q56P). Subsequent validation using shRNA and CRISPR-Cas9 confirmed MAP2K1 dependency. In vitro and in vivo inhibitor studies established that NCI-H1437 cells are sensitive to MEK1 inhibitors, including the FDA-approved drug trametinib. Like NCI-H1437 cells, the MAP2K1 mutant cell lines SNU-C1 (colon) and OCUM-1 (gastric) showed decreased viability after MAP2K1 depletion via Cas9-mediated gene editing. Similarly, these cell lines were particularly sensitive to trametinib treatment compared to control cell lines. Based on these data cancers that harbor driver mutations in MAP2K1 should benefit from treatment with MEK1 inhibitors. Furthermore, this functional data mining approach provides a general method to experimentally test genomic features that confer dependence in tumors.