本团队通过测序技术国际首次报道了新型融合基因PTPRZ1-MET，并针对该基因研发药物用于临床试验，疗效显著。但是，随着药物治疗和肿瘤进展，患者出现耐药，机制尚未明确。前期研究发现，磷酸化STAT3可上调外分泌性蛋白促进血管生成，加速肿瘤增长。进一步大样本数据分析及调研发现，STAT3与肿瘤进展和耐药相关。因此，提出假说：STAT3代偿性激活调控新型PTPRZ1-MET融合基因胶质瘤靶向药物耐药。本项目拟采用生物信息学整合分析、Western Blot、GST Pull-down等方法构建STAT3耐药网络；通过基因回复、细胞功能、免疫组化等实验在体外细胞水平和患者组织中验证耐药机制；利用原位动物模型体内验证并评价干预治疗或逆转耐药可行性；最终揭示“PTPRZ1-MET融合基因—MET信号通路—STAT3代偿性激活”耐药机制。本项目将为融合基因阳性患者的精准治疗提供参考，具有临床转化价值。

Our team firstly reported a novel fusion gene PTPRZ1-MET in the world by sequencing method. We then developed a targeted drug of this gene for clinical trials and achieved significant effect. However, with drug use and tumor progression, patients have showed a certain degree of drug resistance, where the underlying mechanism has not been revealed. Previous study have found that phosphorylated STAT3 could up-regulate exocrine proteins to promote angiogenesis and accelerate tumor growth. Further data analysis and literature review showed that STAT3 was associated with tumor progression and drug resistance. Therefore, we propose a hypothesis that the compensatory activation of STAT3 regulates drug resistance in glioma with PTPRZ1-MET fusion gene. In the present study, we will construct the STAT3 drug resistance network by bioinformatics integration analysis, Western Blot, GST Pull-down and other methods. We will also verify the mechanism of drug resistance using gene recovery, cell function and immunohistochemistry experiments in vitro by cell lines and patient tissues, and evaluate the feasibility of intervention in treatment or reversal of drug resistance in vivo by in situ animal model. Finally, the drug resistance mechanism of “PTPRZ1-MET fusion gene-Met signaling pathway-STAT3 compensatory activation” will be revealed. This study is expected to instruct accurate treatment of fusion gene positive patients, and exhibits potential value of clinical transformation.