MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
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DOI：
10.1038/nature13181
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发表时间：
2014-04-10
期刊：
影响因子：
64.8
通讯作者：
Helleday, Thomas
中科院分区：
文献类型：
--
作者：
Gad, Helge;Koolmeister, Tobias;Helleday, Thomas
癌症具有功能失调的氧化还原调节，导致活性氧产生，破坏DNA和游离dNTP。MTH1蛋白对氧化的dNTP池进行消毒，以防止在DNA复制过程中掺入受损的碱基。虽然MTH1在正常细胞中是非必需的，但我们发现癌细胞需要MTH1活性来避免氧化dNTPs的掺入，从而导致DNA损伤和细胞死亡。我们在体内验证了MTH1作为抗癌靶点，并将小分子TH287和TH588描述为一类营养素水解酶家族抑制剂，其有效地和选择性地参与并抑制细胞中的MTH1蛋白。蛋白质共晶体结构表明，抑制剂结合MTH1的活性位点。这些抑制剂导致氧化的dNTP掺入癌细胞中，导致患者来源的小鼠异种移植物中的DNA损伤、细胞毒性和治疗反应。这项研究阐明了非癌基因成瘾的概念，抗癌治疗和验证MTH1作为癌症表型致死。
Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.