酪氨酸激酶受体配体ERBB4/NRG1突变影响胃癌信号通路及药物反应的机制研究

The ERBB receptors are aberrantly activated in an array of human cancers, they are selected for the anticancer target. We performed whole-exome sequencing on 78 Chinese gastric cancers. The recurrently mutated genes were validated in a separate cohort of 216 cases by targeted sequencing. Date analysis reveal NRG1-ERBB4 ligand-receptor pair were mutated in 10% of gastric cancer cases, and part of mutations locate in key functional domain. However, the mechanism of NRG1-ERBB4 mutations in gastric cancer development and progression and anticancer drug response remains elusive. Firstly, we will study the effect of NRG1-ERBB4 mutations on ligand-receptor binding, kinase activity of receptor, downstream signaling pathways, and cell behavior in cell lines. Secondly, we will study response sensitivity of NRG1-ERBB4 mutations to anticancer drug. Finally, we will study the effect of NRG1-ERBB4 mutations and anticancer drug on tumor growth in animal model. All the findings of NRG1-ERBB4 mutations will elucidate molecular mechanism how mutations and the anticancer drug effect signaling pathway and tumor growth, will provide theoretical basis for identifying potent target in gastric cancer and anticancer drug design based on these sites.

ERBB受体在多种癌症中都存在异常激活，可以作为癌症的治疗靶点。前期对中国人群78例胃癌样本进行了全外显子测序，又对另外216例胃癌样本进行了目标区域测序以验证频发的突变基因，发现NRG1-ERBB4配体-受体在10%的病例中存在突变，且部分突变位于重要功能域，但是这些突变在胃癌发生发展中的功能及其对抗癌药物的反应并不清楚。本项目将首先利用细胞系研究NRG1-ERBB4突变对配体-受体间的结合、受体的激酶活性、下游信号通路转导及细胞行为的影响；然后研究NRG1-ERBB4突变对抗癌药物反应的敏感性；最后利用动物模型研究NRG1-ERBB4突变及抗癌药物对肿瘤生长的影响。这些关于NRG1-ERBB4突变的研究成果将阐明NRG1-ERBB4突变及ERBB抗癌药物影响胃癌中信号通路及肿瘤生长的分子机制，为发现潜在的胃癌治疗靶点和基于这些位点的相关抗癌药物设计提供理论基础。