双重mTORC1/2抑制剂AZD8055在肝癌治疗中的作用及分子机制研究

肝癌是一种多基因参与、多因素介导、病理机制复杂的恶性肿瘤。在临床，Sorafenib和Lenvatinib作为进展期肝癌的标准疗法仅能获得较低的治疗反应性，寻找安全有效的治疗策略已成为肝癌研究领域的重点。本课题前期研究中发现双重mTOR复合物抑制剂AZD8055可导致肝癌细胞发生受体酪氨酸激酶-mTOR信号通路负反馈激活。该负反馈激活作用可能是导致肝癌细胞对mTOR抑制剂不敏感的关键因素。使用酪氨酸磷酸酶SHP2抑制剂阻断该负反馈通路，可以显著促进肝癌细胞凋亡。本研究中，我们拟通过CRISPR功能基因筛选技术系统研究mTOR抑制剂导致该负反馈通路激活的分子机制。同时，在细胞水平明确mTOR抑制剂联合SHP2抑制剂促进肝癌细胞凋亡的作用及分子机制，并在多种肝癌动物模型中探索该治疗策略的可行性。本研究有望为肝癌的治疗提供新思路。

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies with complicated mechanisms of pathogenesis. In the clinic, sorafenib and lenvatinib, as the standard therapy for advanced HCC patients, can only achieve a low therapeutic response rate. Exploring safe and effective treatment strategies has become the focus of liver cancer research. In our previous research, we found that the dual mTORC1 and mTORC2 inhibitor AZD8055 can lead to negative feedback activation of the receptor tyrosine kinase-mTOR signaling pathway in liver cancer cells. This negative feedback activation may be the key factor that causes HCC cells to be insensitive to mTOR inhibitors. Using a tyrosine phosphatase SHP2 inhibitor to block this negative feedback pathway can significantly promote apoptosis of HCC cells. In this study, we are planning to systematically study the molecular mechanism that mTOR inhibitors lead to the activation of this negative feedback pathway through CRISPR-based functional genetic screening. Multiple in vitro and in vivo assays will be used to study the synergistic effects of mTOR inhibition and SHP2 inhibitor. We will also explore the underlying mechanism of the synergistic effects between mTOR inhibitor and SHP2 inhibitor. This study may provide a novel and promising therapeutic approach to the treatment of HCC.