Colorectal cancer: POLR2A deletion with TP53 opens a window of opportunity for therapy.
Colorectal cancer: POLR2A deletion with TP53 opens a window of opportunity for therapy.
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DOI：
10.1038/nrclinonc.2015.94
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发表时间：
2015-07-01
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影响因子：
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通讯作者：
Errico, Alessia
中科院分区：
文献类型：
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作者：
Errico, Alessia
基因组的守护者，肿瘤抑制蛋白P53的失活，在大多数人类肿瘤中很常见。尽管付出了巨大的努力，但还没有一种旨在恢复P53活性的有效疗法成功地应用于临床。现在，陆雄斌和他的同事们强调，TP53及其邻近基因之一POLR2A的共同缺失使癌细胞非常容易受到POLR2A抑制，为包含此类基因组变化的肿瘤提供了一种新的治疗策略。针对肿瘤抑制基因的拷贝数丢失通常涉及邻近的基因，这些基因本身并不对癌症的发展做出贡献，但却产生了一种可用于治疗开发的脆弱性。卢解释说：“POLR2A基因对细胞生存至关重要，在许多人类癌症中，POLR2A基因几乎总是与TP53共缺失，包括结直肠癌、乳腺癌、卵巢癌、肾癌、肝癌和胰腺癌。对癌症基因组图谱数据库的分析显示，几乎所有带有TP53缺失的人类结直肠癌(CRC)中都存在POLR2A的缺失。卢说：“尽管医学研究和手术措施有所改善，但在过去的几十年里，结直肠癌的死亡率几乎没有变化，治疗选择有限，特别是对于含有TP53缺失的结直肠癌。”值得注意的是，编码RNA聚合酶II最大亚基的POLR2a是可药物的，可以被α-Amanitin特异性地抑制。POLR2A半合子缺失导致结直肠癌细胞中RNA聚合酶II的丰度降低，这表明这些细胞比未改变的正常细胞更容易受到α-Amanitin抑制。重要的是，研究人员已经证明，用α-Amanitin(或小干扰RNA)抑制POLR2a可以选择性地抑制带有半合子TP53缺失的结直肠癌细胞的增殖、存活和致瘤潜力，这是一种不依赖于p53的方式。尽管α-Amanitin有很强的抑制作用，但与该药相关的肝脏毒性对其临床开发提出了重大挑战。然而，这种毒性可以通过将α-Amanitin与抗EpCAM的单抗结合来克服，EpCAM是一种细胞表面标记，在腺癌(包括结直肠癌)中富含。值得注意的是，α-Amanitin抗体-药物结合物的使用也提供了靶向性。“我们正计划将我们的α-Amanitin抗体结合物的临床前研究从结直肠癌扩大到其他类型的人类癌症，包括TP53和POLR2A半合子缺失，并寻找其他POLR2A靶向小化合物，”Lu总结道。POLR2A抑制的附带脆弱性原理正在为新的、有望有效的癌症治疗打开一扇机会之窗。
Inactivation of the guardian of the genome, the tumour suppressor protein p53, is common in most human tumours. Despite tremendous efforts, no effective therapy aimed at restoring p53 activity has been successfully translated into the clinic. Now, Xiongbin Lu and colleagues highlight that co-depletion of TP53 and one of its neighbouring genes, POLR2A, renders cancer cells highly vulnerable to POLR2A inhibition, providing a new treatment strategy for tumours containing such genomic changes. Copy-number losses targeting tumour suppressors often involve neighbouring genes that do not contribute to cancer development per se, but nevertheless generate a vulnerability that is exploitable for therapeutic development.“The POLR2A gene is essential for cell survival, and is almost always co-deleted with TP53 in many human cancers, including colorectal, breast, ovarian, kidney, liver, and pancreatic cancer,” explains Lu. Analysis of The Cancer Genome Atlas database has revealed that deletion of POLR2A occurs in virtually all the human colorectal cancers (CRC) with hemizygous TP53 deletion.“Despite improvements in medical research and surgical provision, there has been little change in mortality rates in CRC in the past decades, with limited treatment options, especially for CRC possessing TP53 deletion,” says Lu. Notably, POLR2A, which encodes the largest subunit of RNA polymerase II, is druggable and can be specifically inhibited with α-amanitin. Hemizygous loss of POLR2A results in decreased abundance of RNA polymerase II in CRC cells, suggesting that these cells could be more vulnerable to α-amanitin inhibition than unaltered normal cells. Importantly, the researchers have demonstrated that suppression of POLR2A with α-amanitin (or small interfering RNAs) selectively inhibits the proliferation, survival and tumorigenic potential of CRC cells with hemizygous TP53 loss, in a p53-independent manner. Despite the strong inhibitory effect of α-amanitin, the liver toxicity associated with this agent has presented a major challenge to its clinical development. However, such toxicity can be overcome by the conjugation of α-amanitin with monoclonal antibodies against EpCAM, a cellsurface marker that is enriched in adenocarcinomas, including CRC. Of note, the use of antibody–drug conjugates of α-amanitin also provides targeting specificity.“We are planning to expand our preclinical studies with α-amanitin antibody conjugates from CRC to other types of human cancers with hemizygous loss of TP53 and POLR2A, and search for other POLR2A-targeted small chemical compounds,” concludes Lu. The principle of collateral vulnerability to POLR2A inhibition is opening a window of opportunity for new, and hopefully efficient, cancer therapy.