PTEN-L驱动非小细胞肺癌吉非替尼耐药的分子机制研究

非小细胞肺癌吉非替尼耐药机制研究是目前肺癌研究的重点和难点，尚存有大量临床耐药病例无法用现有机制解释。前期研究中我们发现吉非替尼耐药细胞中EGFR磷酸化水平极低，通过生物质谱分析找到与EGFR结合的PTEN-L，同时发现PTEN-L在吉非替尼耐药细胞中表达较高。体内外预实验结果显示PTEN-L高表达促进非小细胞肺癌细胞对吉非替尼的耐受。PTEN-L结合EGFR通过其蛋白磷酸酶功能降低EGFR磷酸化水平，维持EGFR低活性状态。此外，PTEN-L可与PTEN结合，使PTEN（Y336）发生去磷酸化，降低PTEN蛋白稳定性，拮抗PTEN的抑癌功能，促进具有低活性EGFR信号的细胞维持其恶性特征。本研究将深层次解析PTEN-L多步骤多层面驱动非小细胞肺癌吉非替尼耐药的分子机制，并与临床相结合，为非小细胞肺癌吉非替尼的治疗选择提供新的标记物，以及为吉非替尼耐药后的治疗提供新靶标。

The study of gefitinib resistance mechanism in non-small cell lung cancer is the focus and difficulty of current lung cancer research. There are still a large number of clinical drug resistance cases that cannot be explained by the existing mechanisms. In the previous study, we found that the EGFR phosphorylation level in gefitinib-resistant cells was extremely low. The phosphatase PTEN-L was most likely to bind to EGFR through the screening of biomass spectrometry, and the detection of PTEN-L in gefitinib-resistant cells was found to be highly expressed. Further in vivo and in vitro preliminary experiment results show that high expression of PTENα promotes the resistance of non-small cell lung cancer cells to gefitinib. The above results indicate that PTEN-L has an important biological function in the gefitinib resistance in non-small cell lung cancer. At the molecular level, PTEN-L binds to EGFR to reduce the level of EGFR phosphorylation through its protein phosphatase function and maintain the low activity of EGFR signals. In addition, PTEN-L can bind to PTEN,causing the dephosphorylation of PTEN (Y336), reducing the stability of PTEN protein, antagonizing the anti-cancer function of PTEN, and promoting the cells with weak EGFR signals to continue to maintain their malignant characteristics. This study will deeply analyze the multi-step and multi-level molecular mechanisms of PTEN-L driving gefitinib resistance in non-small cell lung cancer, and combine it with clinical practice to provide a new marker for treatment selection of gefitinib and a new target for treatment after gefitinib resistance.