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摘要 : 肿瘤抑制基因TP53在绝大多数人类肿瘤中都会因突变或删除而失活。迄今为止,试图恢复其产物p53的活性的努力都由于p53信号传导的复杂性而鲜有获得成功的。这篇论文提出了一个间接定位TP53的新方法。

 肿瘤抑制基因TP53在绝大多数人类肿瘤中都会因突变或删除而失活。迄今为止,试图恢复其产物p53的活性的努力都由于p53信号传导的复杂性而鲜有获得成功的。这篇论文提出了一个间接定位TP53的新方法。TP53的基因组删除经常包括其他相邻基因,如POLR2A “管家基因”(它编码一个关键的“RNA聚合酶II”亚单元)。Xionbin Lu及同事发现,一个版本的POLR2A的失去会使癌细胞对“RNA聚合酶II”抑制剂(如α--amanitin)高度敏感。在关于癌症的小鼠模型中,含POLR2A/TP53共删除(co-deletion)的肿瘤可以通过与以癌细胞为目标的抗体共轭的α--amanitin被选择性地定位。对于影响必要的“管家”(housekeeping)功能的除肿瘤抑制基因以外的其他基因组删除,也对选择性脆弱性(vulnerability)加以利用,也许能够为一系列不同的癌症采用选择性疗法铺平道路。


TP53 loss creates therapeutic vulnerability in colorectal cancer


TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by α-amanitin8, 9. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with α-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited owing to its liver toxicity10. However, we found that α-amanitin-based antibody–drug conjugates are highly effective therapeutic agents with reduced toxicity11. Here we show that low doses of α-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.

来源: Nature 浏览次数:1


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