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的机制研究

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.

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。

胶质瘤是颅内最常见的原发性恶性肿瘤，由于其弥漫性生长模式及大脑功能的特殊性，手术难以完全切除。胶质瘤的恶性进展往往是遗传基因变异而导致其对化疗药物替莫唑胺的抵抗，使得综合治疗效果不佳。本团队通过测序技术国际首次报道了新型融合基因PTPRZ1-MET（ZM），阐明了该基因导致肿瘤恶性进展的机制并以此为靶点研发药物用于临床试验，疗效显著。但是，患者在靶向治疗后出现复发，机制尚未明确。本研究发现，长期使用靶向药物治疗，肿瘤细胞会耐药复发，细胞中Stat3通路被激活，细胞增殖活力、细胞粘附等恶性表型恢复。进一步研究发现，虽然Stat3通路激活，但并不是导致细胞耐药的主要原因。抑制整合素通路可恢复肿瘤细胞对靶向药物的敏感性，有效控制疾病进展。本项目的重要意义在于：探索了ZM融合基因阳性胶质瘤患者在靶向治疗过程中的基因变化，以期为该类患者的临床治疗提供新的靶点和思路。目前，受本项目资助，已发表SCI论文四篇，中文核心期刊论文两篇。在本项目的培养和支持下，负责人通过了副研究员的职称晋升，参与编写专著一部，与团队获得省部级奖励一项。

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