TP53 loss creates therapeutic vulnerability in colorectal cancer
TP53 loss creates therapeutic vulnerability in colorectal cancer
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DOI：
10.1038/nature14418
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发表时间：
2015-04-30
期刊：
影响因子：
64.8
通讯作者：
Lu, Xiongbin
中科院分区：
文献类型：
--
作者：
Liu, Yunhua;Zhang, Xinna;Lu, Xiongbin
TP 53是一种众所周知的肿瘤抑制基因，编码p53，在大多数人类肿瘤中经常因突变或缺失而失活。人们已经做出了巨大的努力来恢复癌症治疗中的p53活性。然而，由于p53信号传导的复杂性，没有有效的基于p53的疗法成功地转化为临床癌症治疗。在这里，我们证明，基因组缺失的TP 53经常包括必要的相邻基因，使癌细胞与半合子TP 53缺失易受进一步抑制的基因。POLR 2A被鉴定为在人类癌症中几乎总是与TP 53共缺失的基因。它编码RNA聚合酶II复合物的最大催化亚基，该复合物被α-鹅膏蕈碱特异性抑制。我们对癌症基因组图谱（TCGA）和癌细胞系百科全书（CCLE）数据库的分析表明，POLR 2A表达水平与其在人类结直肠癌中的基因拷贝数密切相关。用α-鹅膏蕈碱或小干扰RNA抑制POLR 2A以p53非依赖性方式选择性抑制具有半合子TP 53缺失的结直肠癌细胞的增殖、存活和致瘤潜力。由于其肝毒性，α-鹅膏蕈碱的先前临床应用受到限制。然而，我们发现基于α-鹅膏蕈碱的抗体-药物缀合物是具有降低的毒性的高效治疗剂。在这里，我们表明，低剂量的α-鹅膏蕈碱结合的抗上皮细胞粘附分子（EpCAM）抗体导致完全肿瘤消退的人结肠直肠癌与POLR 2A的半合子缺失的小鼠模型。我们预计，抑制POLR 2A将是一种新的治疗方法，用于治疗含有这种常见基因组改变的人类癌症。
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 a-amanitin". 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 alpha-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 a-amanitin have been limited owing to its liver toxicity'. However, we found that alpha-amanitin-based antibody-drug conjugates are highly effective therapeutic agents with reduced toxicity". Here we show that low doses of alpha-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.