阿帕替尼是VEGFR2小分子络氨酸激酶抑制剂，能够有效抑制肿瘤血管生成，目前已被CFDA批准治疗化疗失败的晚期胃癌。然而，抗血管生成药物的耐药现象十分普遍且机制不明，成为该类药物临床应用的最大瓶颈。本项目前期通过建立胃癌阿帕替尼耐药动物模型，发现趋化因子CXCL5参与介导胃癌阿帕替尼原发耐药。随后研究发现CXCL5能够通过转录因子STAT3调控ERK启动子活性，但具体作用机制仍不清楚。本项目拟在前期工作的基础上，采用RNA干扰技术、重组质粒调控技术、双荧光素报告基因及染色质免疫共沉淀等技术，从分子、细胞和动物水平明确CXCL5 /STAT3/ERK信号网络在阿帕替尼耐药中的作用及其之间的调控机制，并利用II/III期临床试验标本考察CXCL5、STAT3、ERK等对于阿帕替尼疗效的预测作用，期望对提高胃癌抗血管生成疗效提供有价值的参考。

Apatinib, a small molecular VEGFR2 tyrosine kinase inhibitor, has been approved by CFDA for treatment of late-stage gastric cancer. However, anti-angiogenesis therapy resistance is commonly happened in clinical practice and has become a big obstacle for patient treatment. Thus, it is urgent and necessary to find out biomarker as well as molecular mechanism on anti-angiogenesis therapy resistance. Previously, through establishing apatinib resistance model in vivo, we found CXCL5 could enhance angiogenesis and mediate apatinib drug resistance in gastric cancer. Also, we found that CXCL5 upregulated STAT3 activity which regulated ERK promoter. In the present study, we aimed to further study the molecular mechanism on CXCL5 mediated drug resistance. We will using in vitro and in vivo experiments such as RNAi, recombinant plasmid transfection, dual luciferase report gene and chromatin immunoprecitation to evaluate the value of signal pathway CXCL5/STAT3/ERK in apatinib drug resistance. Therefore, using clinical samples from II/III clinical trials, we would evaluate the prognostic value of CXCL5,JAK2 and ERK on apatinib treatment. In conclusion, our study might provide solid and important evidence to find the biomarker to predict apatinib drug efficacy in gastric cancer.