衰老型CAFs通过外泌体miR-221靶向激活PTEN/PI3K/AKT信号通路促进肺癌对MLN4924抗药性的机制研究

Neddylation是一种新型蛋白翻译后修饰方式，在多种肿瘤中过度活化并促进肿瘤发生，而阻断此通路具有显著抗肿瘤作用。NEDD8抑制剂MLN4924已进入I/II/III期临床试验，显示出良好的应用前景。近来研究报道，MLN4924联合用药较单药可明显增强抗肿瘤效应。我们前期研究发现，抑制肺癌Neddylation通路可诱导肿瘤相关成纤维细胞（CAFs）发生衰老，后者可通过外泌体富集的miR-221促进肺癌细胞的增殖及转移，提示衰老型CAFs可能促使肺癌产生对MLN4924的抗性。该项目拟研究衰老型CAFs来源的外泌体通过miR-221激活PTEN/PI3K/AKT通路促进肺癌发生发展的作用机制。本项目的顺利实施将揭示肺癌微环境内衰老型CAFs与肿瘤细胞的相互作用，为探索通过阻断PTEN/PI3K/AKT通路增强MLN4924的联合治疗提供科学依据。

Neddylation is a novel protein post-translational modification, which is over activated and promotes tumorigenesis in a variety of tumors. Blocking this pathway has a significant anti-tumor effect. The Nedd8 inhibitor mln4924 has entered the phase I / II / III clinical trials, showing a good application prospect. Recently, it has been reported that mln4924 can significantly enhance the anti-tumor effect compared with single drug. Our previous study found that inhibition of neddylation pathway in lung cancer can induce the senescence of tumor associated fibroblasts (CAFs), which can promote the proliferation and metastasis of lung cancer cells through mirna-221 in exosomes, suggesting that senescent CAFs may promote lung cancer resistance to MLN4924. This project aims to study the mechanism of senescent CAFs promoting the development of lung cancer by enriching exocrine mirna-221 and activating PTEN / PI3K / Akt pathway. The successful implementation of this project will reveal the cross-talk between senescent CAFs and tumor cells in lung cancer microenvironment, and provide scientific basis for exploring the combination therapy of enhancing mln4924 by blocking PTEN / PI3K / Akt pathway.