Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses
Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses
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DOI：
10.1073/pnas.0808757105
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发表时间：
2008-12-30
影响因子：
11.1
通讯作者：
Bardelli, Alberto
中科院分区：
文献类型：
--
作者：
Di Nicolantonio, Federica;Arena, Sabrina;Bardelli, Alberto
癌基因和肿瘤抑制基因的突变是肿瘤发生的原因，并且是肿瘤学中理想的治疗靶点。我们利用同源重组技术在未转化的人类细胞基因组中敲入单个癌症突变。还实现了多个突变的顺序引入，证明了这种策略在构建肿瘤进展模型方面的潜力。敲入细胞显示出信号通路的等位基因特异性激活以及不同于通过异位癌基因表达所能获得的突变特异性表型。对突变细胞的药物库进行分析表明，对靶向通路的药物表现出显著的敏感或耐药表型，这些表型通常与携带相同癌症突变的肿瘤细胞相匹配。因此，单个或多个癌症等位基因的敲入为合理设计靶向治疗提供了一个药物基因组学平台。
Mutations in oncogenes and tumor suppressor genes are responsible for tumorigenesis and represent favored therapeutic targets in oncology. We exploited homologous recombination to knock-in individual cancer mutations in the genome of nontransformed human cells. Sequential introduction of multiple mutations was also achieved, demonstrating the potential of this strategy to construct tumor progression models. Knock-in cells displayed allele-specific activation of signaling pathways and mutation-specific phenotypes different from those obtainable by ectopic oncogene expression. Profiling of a library of pharmacological agents on the mutated cells showed striking sensitivity or resistance phenotypes to pathway-targeted drugs, often matching those of tumor cells carrying equivalent cancer mutations. Thus, knock-in of single or multiple cancer alleles provides a pharmacogenomic platform for the rational design of targeted therapies.