Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions
Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions
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DOI：
10.1172/jci37127
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发表时间：
2009-06-01
影响因子：
15.9
通讯作者：
Thomas, Roman K.
中科院分区：
文献类型：
--
作者：
Sos, Martin L.;Michel, Kathrin;Thomas, Roman K.
癌症中的体细胞遗传改变通过产生对激活的致癌信号传导途径的特异性依赖性而与对靶向治疗的反应相关联。然而，目前还没有工具系统地将这种遗传损伤与治疗脆弱性联系起来。因此，我们开发了一种基因组学方法来识别与治疗相关的癌基因依赖性相关的病变。使用整合的基因组分析，我们已经证明，一个大的面板的人非小细胞肺癌（NSCLC）细胞系的基因组是高度代表的原发性NSCLC肿瘤。使用基于细胞的化合物筛选加上不同的计算方法来整合正交基因组和生化数据集，我们确定了临床相关化合物的治疗反应的分子和基因组预测因子。使用这种方法，我们表明v-Ki-ras 2 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变赋予增强的Hsp 90依赖性，并在KRAS驱动的肺腺癌小鼠中验证了这一发现，因为这些小鼠在用Hsp 90抑制剂治疗时表现出显著的肿瘤消退。此外，我们发现，v-abl Abelson小鼠白血病病毒癌基因同源物2（ABL 2）和肝配蛋白受体激酶和v-src肉瘤（Schmidt-Ruppin A-2）病毒癌基因同源物（禽类）（SRC）激酶家族基因拷贝数增加的细胞对SRC/ABL抑制剂达沙替尼治疗非常敏感，无论是在体外还是异种移植到小鼠体内。因此，基因组注释的细胞系集合可以通过定义服从治疗抑制的关键途径依赖性来帮助将癌症基因组学信息转化为临床实践。
Somatic genetic alterations in cancers have been linked with response to targeted therapeutics by creation of specific dependency on activated oncogenic signaling pathways. However, no tools currently exist to systematically connect such genetic lesions to therapeutic vulnerability. We have therefore developed a genomics approach to identify lesions associated with therapeutically relevant oncogene dependency. Using integrated genomic profiling, we have demonstrated that the genomes of a large panel of human non-small cell lung cancer (NSCLC) cell lines are highly representative of those of primary NSCLC tumors. Using cell-based compound screening coupled with diverse computational approaches to integrate orthogonal genomic and biochemical data sets, we identified molecular and genomic predictors of therapeutic response to clinically relevant compounds. Using this approach, we showed that v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations confer enhanced Hsp90 dependency and validated this finding in mice with KRAS-driven lung adenocarcinoma, as these mice exhibited dramatic tumor regression when treated with an Hsp90 inhibitor. In addition, we found that cells with copy number enhancement of v-abl Abelson murine leukemia viral oncogene homolog 2 (ABL2) and ephrin receptor kinase and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) kinase family genes were exquisitely sensitive to treatment with the SRC/ABL inhibitor dasatinib, both in vitro and when it xenografted into mice. Thus, genomically annotated cell-line collections may help translate cancer genomics information into clinical practice by defining critical pathway dependencies amenable to therapeutic inhibition.