Department of Gastroenterology and Hepatology, Erasmus Medical University Center, Rotterdam, The Netherlands.
Oncogene. 2011 May 19;30(20):2289-303. doi: 10.1038/onc.2010.630. Epub 2011 Jan 24.
The liver kinase B1 (LKB1)/adenosine mono-phosphate-activated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the Peutz-Jeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.
肝激酶 B1（LKB1）/腺苷单磷酸激活蛋白激酶（AMPK）/结节性硬化复合物（TSC）/雷帕霉素靶蛋白（mTOR）复合物（mTORC1）盒构成了一个经典的信号通路，它整合了代谢和营养状况的信息，并将其转化为细胞生长的调节。该通路的改变与多种癌症和遗传性错构瘤综合征有关，这些疾病中已经描述了 mTORC1 的过度激活。已经开发出了用于临床应用的特定 mTORC1 抑制剂，并且这些药物有望为这些疾病提供有效的治疗。在本综述中，我们概述了代谢 LKB1/AMPK/TSC/mTORC1 通路，描述了其异常信号如何与癌症发展相关联，并指出了在将生化数据推断为靶向该信号通路进行疾病合理治疗时所遇到的困难。对使用雷帕霉素或其衍生物进行的临床前和临床研究的仔细检查表明，尽管结果令人鼓舞，但我们仅完成了设计针对 LKB1/AMPK/TSC/mTORC1 通路的合理治疗的漫长而曲折的道路的一半。与该通路相关的遗传性癌症综合征，如 Peutz-Jeghers 综合征和 TSC，为研究遗传与疾病表型之间的关系以及阐明将生化和遗传信息转化为临床管理的复杂性提供了完美的模型，从而为设计针对癌症疾病的新型合理药物提供了重要线索。
