鉴定大肠癌中非依赖于mTOR的4E-BP1蛋白激酶的实验研究

4E-BP1被认为是mTOR激酶的经典底物。但我们的先期研究发现，在人大肠癌，mTOR可能并非4E-BP1的唯一激酶；非依赖于mTOR的4E-BP1磷酸化可能介导大肠癌对mTOR激酶抑制剂（mTKIs）耐药。由此，我们提出理论假设：在mTKIs耐药大肠癌存在特异的非依赖于mTOR的4E-BP1蛋白激酶（mTOR Independent 4E-BP1 Kinase, TIEK）；TIEK所介导的4E-BP1磷酸化赋予细胞对mTKIs的耐药性；抑制TIEK，可逆转大肠癌对mTKIs的耐药。本项目将在以往的工作基础上进一步鉴定除mTOR以外的4E-BP1蛋白激酶，揭示TIEK的真实身份，明确TIEK磷酸化4E-BP1的信号路径，探讨通过干预TIEK逆转大肠癌对mTKIs耐药的可行性。其实施将有助于阐释4E-BP1蛋白磷酸化的调节机制，对于大肠癌的发生发展机理探讨、以及分子靶向治疗等均具重要意义。

4E-BP1 is a major mTORC1 substrate that plays a pivotal role in mTORC1 signaling to control translation and cell proliferation. We reported previously that mTOR is not the only kinase for 4E-BP1 phosphorylation, and an mTOR-independent 4E-BP1 phosphorylation is strongly correlated with colorectal cancer (CRC) resistance to mTKIs (ATP competitive mTOR kinase inhibitor). Here we proposed that there is specific mTOR independent 4E-BP1 kinase (TIEK) in human CRC, which is responsible for mTOR independent 4E-BP1 phosphorylation, and contributes to resistance to mTKIs. This proposal aimed at identification of the alternative kinase responsible for mTOR independent 4E-BP1 phosphorylation, elucidating the TIEK/4E-BP1 signal transduction pathway, and answering whether TIEK inhibition could overcome resistance to mTKIs. This project may provide fundamental evidence to clarify the mechanism for mTOR independent 4E-BP1 phosphorylation. The results of this study will contribute to translate laboratory discoveries into important new clinical tools and applications that will improve the target therapy of CRC.