The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer
The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer
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DOI：
10.1016/j.cell.2012.02.059
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发表时间：
2012-04-27
期刊：
影响因子：
64.5
通讯作者：
Downward, Julian
中科院分区：
文献类型：
--
作者：
Kumar, Madhu S.;Hancock, David C.;Downward, Julian
非小细胞肺癌（NSCLC）是全球癌症死亡的最常见原因;近一半在受体酪氨酸激酶/RAS通路中含有突变。在这里，我们表明RAS途径突变的NSCLC细胞依赖于转录因子GATA 2。GATA 2的缺失降低了RAS途径突变的NSCLC细胞的活力，而野生型细胞不受影响。综合基因表达和基因组占有率分析揭示了GATA 2调节蛋白酶体、IL-1信号传导和Rho信号传导途径。这些途径在功能上是重要的，因为在GATA 2耗尽后重新激活挽救了活力。在Kras驱动的NSCLC小鼠模型中，Gata 2丢失显著降低了肿瘤的发展。此外，在已建立的Kras突变肿瘤中Gata 2缺失诱导显著的消退。虽然GATA 2本身可能是不可用药的，但GATA 2调节途径与临床批准的抑制剂的组合抑制引起显著的肿瘤清除。KRAS突变肺癌对GATA 2的非癌基因成瘾的发现提出了用于治疗开发的可药物化途径的网络。
Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide; nearly half contain mutations in the receptor tyrosine kinase/RAS pathway. Here we show that RAS-pathway mutant NSCLC cells depend on the transcription factor GATA2. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected. Integrated gene expression and genome occupancy analyses revealed GATA2 regulation of the proteasome, and IL-1-signaling, and Rho-signaling pathways. These pathways were functionally significant, as reactivation rescued viability after GATA2 depletion. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development. Furthermore, Gata2 deletion in established Kras mutant tumors induced striking regression. Although GATA2 itself is likely undruggable, combined suppression of GATA2-regulated pathways with clinically approved inhibitors caused marked tumor clearance. Discovery of the nononcogene addiction of KRAS mutant lung cancers to GATA2 presents a network of druggable pathways for therapeutic exploitation.