CXCL5及其受体调控JAK2/STAT3信号通路介导胃癌抗血管生成治疗耐药的机制研究

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.

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。

抗血管生成治疗作为胃癌诊疗策略中的重要组成，近年来备受关注。阿帕替尼，是一种VEGFR2小分子络氨酸激酶抑制剂，已经被CFDA批准成为晚期胃癌三线标准治疗。然而，关于抗血管生成药物耐药的相关机制，目前尚无定论。本课题主要是探索了CXCL5及其受体调控JAK2/STAT3信号通路介导的胃癌阿帕替尼耐药的机制。（1）体外实验证实，调控CXCL5/CXCR2-JAK2/STAT3-MAPK/ERK信号通路的关键靶分子，能够影响胃癌细胞体对于阿帕替尼的敏感性；（2）体内试验证实，CXCR2通路抑制剂在体内能够显著增敏阿帕替尼的抑瘤作用，说明共靶向CXCL5/CXCR2及VEGFA/VEGFR2通路能够起到协同抑瘤作用；（3）临床样本证实，CXCL5/CXCR2-JAK2/STAT3-MAPK/ERK信号通路关键靶分子能够预测胃癌阿帕替尼疗效。本课题研究了CXCL5介导的抗血管生成药物阿帕替尼原发耐药的机制，同时也探索了如 CXCL5、STAT3、ERK等潜在关键分子在阿帕替尼临床应用疗效预测方面的应用前景，为胃癌抗血管生成治疗优势人群的筛选提供参考，具有良好的理论意义和临床转化价值。