曲妥珠单抗是目前唯一被证实对HER2阳性胃癌有效的分子靶向药物，其联合化疗能显著延长患者的生存期，但有效率仅47%，且12%的患者对曲妥珠单抗原发耐药，中位疾病控制时间仅6.7个月，患者最终都会对曲妥珠单抗产生耐药性。针对HER2阳性胃癌对曲妥珠单抗耐药的确切机制，目前尚未见报道。我们前期工作通过动态监测接受曲妥珠单抗治疗的HER2阳性胃癌患者的循环血ctDNA，对循环血ctDNA中416个耐药相关基因的外显子进行测序，结果发现1型神经纤维瘤病（NF1）基因突变可导致HER2阳性胃癌对曲妥珠单抗产生耐药性，进一步分析显示，部分NF1基因突变（第6号外显子E217X截短突变）可导致NF1抑癌功能发生缺失，导致RAS-GTP水平升高，激活RAS下游通路。本项目拟进一步在体内外探索NF1基因突变/缺失导致HER2阳性胃癌对曲妥珠单抗耐药的分子机制及寻找克服耐药的新方法，指导胃癌的精准治疗。

Trastuzumab is currently proved to be the only effective targeted drug against HER2-positive gastric cancer. Combined with chemotherapy, trastuzumab can significantly improve the overall survival, but the response rate is only 47% and 12% of patients are resistant to trastuzumab primarily and the median progression free survival is only 6.7 months. All the patients will eventually acquire resistance to trastuzumab. Until now, the exact mechanism of resistance to trastuzumab in HER2-positive gastric cancer is still unknown. In our pilot study, the circulating tumor DNA (ctDNA) in patients with HER2-positive gastric cancer who were given trastuzumab treatment were dynamically monitored. The exons of ctDNA in 416 drug resistance-related genes were sequenced and found that the type 1 neurofibromatosis (NF1) gene mutations may mediate trastuzumab resistance. Further analysis showed that NF1 gene mutations (E217X truncation mutation in NF1 exon 6) may lead to dysfunction of NF1, elevation of RAS-GTP level, activation of RAS downstream pathways, all of which will results in tumor proliferation. Our present study are to further explore the molecular mechanisms of NF1 gene mutations mediated trastuzumab resistance in HER2-positive gastric cancer in vitro and in vivo and look for the new strategies to overcome trastuzumab resistance in HER2-positive gastric cancer.