新型HER3中和抗体逆转胃癌细胞曲妥珠单抗耐药的机制研究

Efficacy of systematic chemotherapy in advanced gastric cancer has reached its bottleneck, till the introduction of target agents. Those targets include HER family and c-MET signal pathway. Trastuzumab has become the first and only approved anti-HER2 antibody in advanced gastric carcinoma since it improves overall survival of HER2 overexpressed gastric cancer. However, the response of trastuzumab combined with chemotherapy remains 47.3%, it would be clinical importance to discuss the mechanism of resistance and the possibility to reverse.In HER2 driven tumors, PI3K/AKT pathway is activated by both HER3 and c-MET. Anti-HER3 is possible to reverse the resistance to trastuzumab, and block the c-MET pathway as well. In this study, we would treat gastric cancer cell lines resistant to trastuzumab with new anti-HER3 antibody, to observe the interactions and poly signal transduction between HER3 and its ligand NRG1, HER2 and c-MET. Based on result, we would try to explain the role of HER3 in proliferation and progression of gastric cancer, and the mechanism of trastuzumab resistance reversal by anti-HER3 antibody.

传统化疗药物治疗晚期胃癌达到瓶颈，分子靶向药物可提高胃癌整体治疗水平,HER家族及c-MET信号传导通路成为胃癌治疗关键通路。抗HER2单抗成为迄今为止唯一在晚期胃癌治疗中确认有生存获益的靶向药物，但其联合化疗的客观有效率也仅47.3%，意味着仍有过半患者未能从其中获益。因此探讨其耐药机制并尝试进行逆转具有重要的基础及临床意义。在HER2驱动肿瘤中，PI3K/AKT通路主要通过HER3的信号激活，该通路也是c-MET下游传导途径。HER3阻断治疗可能与抗HER2治疗产生协同，逆转抗HER2治疗耐药，也可能同时阻断c-MET信号传导通路，成为胃癌治疗的新靶点。本研究拟通过新型HER3中和抗体，以曲妥珠单抗耐药胃癌细胞株为研究对象，探究HER3与配体NRG1、膜受体HER2和c-MET之间相互作用，并由此引发的多重信号传导，试图阐明HER3在胃癌的增殖演进及逆转曲妥珠单抗耐药治疗胃癌的机制。

目的 在体内外水平上探讨HER3抗体联合曲妥珠单抗在HER2阳性胃癌中的作用与机制。方法 体外研究使用HER2阳性细胞系NCI-N87，以及HER2阴性细胞系SGC7901，MTS法检测细胞增殖曲线及Western Blot检测HER2下游信号通路变化。使用NCI-N87移植瘤模型、HER2阳性和HER2阴性胃癌患者胃镜活检组织构建的人源化胃癌移植瘤（PDX）模型，在体内外水平评价HER3抗体（3D4+1A5）和曲妥珠单抗单独或联合给药时对肿瘤的抑制作用。结果 在体内外水平上，HER3抗体联合曲妥珠单抗在HER2阳性胃癌中有明显的协同作用，在HER2阴性细胞系及HER2阴性PDX中无明显单药及协同抑制作用。HER3抗体与曲妥珠单抗对HER2阳性胃癌的协同抑制作用是通过抑制HER2下游信号通路，降低pAKT、pERK、pS6水平实现的。结论 本研究在体内外水平上证实了HER3抗体与曲妥珠单抗在HER2阳性胃癌中具有协同抗肿瘤作用。