ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer.
ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer.
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DOI：
10.1126/sciadv.aar3938
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发表时间：
2018-09
期刊：
影响因子：
13.6
通讯作者：
Grosveld GC
中科院分区：
文献类型：
--
作者：
Harwood FC;Klein Geltink RI;O'Hara BP;Cardone M;Janke L;Finkelstein D;Entin I;Paul L;Houghton PJ;Grosveld GC
由ETS转录因子ETV7组装的一个新的mTOR复合体与肿瘤对雷帕霉素的耐药性有关。雷帕霉素(MTOR)丝氨酸/苏氨酸激酶是细胞增殖的关键调节因子，在人类癌症中经常被解除调控。尽管雷帕霉素可以抑制mTORC1和mTORC2这两种典型的mTOR复合体，但作为抗癌药物，它的益处往往微乎其微。这是由许多不同肿瘤的雷帕霉素耐药引起的，我们发现第三个mTOR复合体mTORC3参与了这种耐药。E26转化特异性转录因子EtV7与细胞质中的mTOR相互作用，组装mTORC3，而mTORC3不依赖于EtV7的S转录活性。该复合体表现出双峰mTORC1/2活性，但缺乏关键的mTORC1/2组分。许多人类癌症以相当高的频率激活mTORC3，失去mTORC3表达的肿瘤细胞系对雷帕霉素变得敏感。我们在横纹肌肉瘤小鼠模型中显示了mTORC3‘S的致瘤性，在该模型中，转基因ETV7的表达加速了肿瘤的发生并促进了肿瘤的侵袭。MTORC3的发现代表了mTOR范式的转变，并确定了抗癌药物开发的新靶点。
A novel mTOR complex assembled by the ETS transcription factor ETV7 contributes to rapamycin resistance in cancer. The mechanistic target of rapamycin (mTOR) serine/threonine kinase, a critical regulator of cell proliferation, is frequently deregulated in human cancer. Although rapamycin inhibits the two canonical mTOR complexes, mTORC1 and mTORC2, it often shows minimal benefit as an anticancer drug. This is caused by rapamycin resistance of many different tumors, and we show that a third mTOR complex, mTORC3, contributes to this resistance. The ETS (E26 transformation–specific) transcription factor ETV7 interacts with mTOR in the cytoplasm and assembles mTORC3, which is independent of ETV7’s transcriptional activity. This complex exhibits bimodal mTORC1/2 activity but is devoid of crucial mTORC1/2 components. Many human cancers activate mTORC3 at considerable frequency, and tumor cell lines that lose mTORC3 expression become rapamycin-sensitive. We show mTORC3’s tumorigenicity in a rhabdomyosarcoma mouse model in which transgenic ETV7 expression accelerates tumor onset and promotes tumor penetrance. Discovery of mTORC3 represents an mTOR paradigm shift and identifies a novel target for anticancer drug development.
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