YAP在ROS1阳性NSCLC靶向治疗耐药中的作用及机制研究

It has important clinical significance to study the mechanism of drug resistance in ROS1-rearranged non–small cell lung cancer (NSCLC), and to search for new therapeutic targets. YAP has been proved to be associated with anti-tumor drug resistance in multiple tumors; however, whether YAP is involved in the crizotinib resistance of ROS1-rearranged NSCLC remains unclear. In our previous study, YAP, LC3-II and O-β-(N-acetyl) glucosamine transferase (OGT) levels were observed to be increased in pleural effusion and tissue specimens of ROS1-rearranged crizotinib-resistant NSCLC patients and ROS1-rearranged crizotinib-resistant cell line (HCC78CR). After blocking OGT in HCC78CR, the expression of YAP and autophagy related genes and proteins decreased, and the cells were resensitized to crizotinib treatment. Based on these results, we speculate that O-GlcNAc modification (OGM) could regulate autophagy via YAP, and induce drug resistance. For the purpose of providing theoretical basis and new treatment ideas in overcoming drug resistance of ROS1-rearranged NSCLC, we plan to utilize in vitro cellular experiments and in vivo nude-mouse transplanted tumor models to investigate the following issues: (1) the function and regulating mechanism of YAP, OGM and autophagy in the crizotinib resistant ROS1-rearranged NSCLC; (2) therapeutic effect of YAP-targeted and autophagy-targeted inhibitors in ROS1-rearranged crizotinib-resistant NSCLC.

研究ROS1阳性非小细胞肺癌（NSCLC）靶向治疗耐药机制，寻找新的治疗靶点具有重要临床意义。YAP被证实参与多种肿瘤的抗肿瘤耐药，但其是否参与ROS1阳性NSCLC的靶向治疗耐药尚不清楚。我们前期研究发现ROS1突变且克唑替尼耐药的NSCLC患者胸水、肺癌组织、肺癌细胞株HCC78CR中YAP、LC3-II、O-GlcNAc糖基化转移酶（OGT）均高表达。在HCC78CR中阻断OGT后，YAP和自噬通路相关分子表达均降低，细胞重新对克唑替尼治疗敏感，推测O-linked-β-N-乙酰葡萄糖胺糖基化修饰（OGM）可通过YAP调控自噬导致耐药的形成。我们拟通过体外细胞及体内裸鼠移植瘤模型研究：（1）YAP、OGM、自噬在ROS1阳性NSCLC克唑替尼治疗耐药中作用及调控机制；（2）以YAP和自噬为治疗靶点治疗ROS1阳性克唑替尼耐药NSCLC的疗效，为克服耐药提供理论依据和新的治疗思路。

YAP被证实参与多种肿瘤的进展及抗肿瘤耐药。我们前期研究发现ROS1突变且克唑替尼耐药的NSCLC患者胸水、肺癌组织、肺癌细胞株HCC78CR中YAP、LC3-II、O-GlcNAc糖基化转移酶（OGT）均高表达。在HCC78CR中阻断OGT后，YAP和自噬通路相关分子表达均降低，细胞重新对克唑替尼治疗敏感，推测O-linked-β-N-乙酰葡萄糖胺糖基化修饰（OGM）可通过调控YAP促进肿瘤进展及耐药的形成。我们通过体外细胞及体内裸鼠移植瘤模型研究发现：（1）O-GlcNAc糖基化水平升高促进YAP的O-GlcNAc糖基化修饰及YAP入核，YAP入核后通过调控FOXM1的表达促进肺癌进展；（2）YAP抑制剂Verteporfin可显著延缓肿瘤生长，抑制肿瘤转移。综上，YAP可被作为肺癌治疗新靶点。