基于BAFF/MyD88/NIK的非经典型NF-κB信号通路调控淋巴瘤对BTK抑制剂ibrutinib的疗效及其机制研究

Nuclear factor κB (NF-κB) signal pathway got even more attention after Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib received the U.S. Food and Drug Administration (FDA)'s breakthrough therapy designation for the treatment of two subtypes of B-cell lymphoma. Clinical studies showed Ibrutinib targeting the canonical NF-κB pathway was effective in only part of lymphoma patients. Our previous research suggested BAFF/MyD88/NIK non-canonical NF-κB pathway involved in the resistance. The project would observe the effects of BAFF neutralizing antibody, MyD88 inhibitors and NIK / IKKα inhibitors in the combination with Ibrutinib, respectively, and the combination inducing cell cycle arrest, apoptosis and autophagy in lymphoma cell lines. Using gene sequencing, Western blot, immunoprecipitation, RNA interference and ELISA techniques, we would found the synergistic effects and mechanisms of targeting BAFF/MyD88/NIK of the non-canonical NF-κB pathway in the combination of Ibrutinib targeting the canonical NF-κB pathway in vitro and in vivo. Predictive biomarkers of the synergistic effect of the combination also would be found. A solid basis of the optimal combination of targeted therapies of the non-canonical NF-κB pathway with the canonical NF-κB pathway will be explored.

随着布鲁顿酪氨酸激酶(BTK)抑制剂Ibrutinib以2013年"突破性治疗药物"获美国批准治疗B细胞性淋巴瘤的两种亚型，核因子-κB(NF-κB)信号通路更受关注。临床研究显示，靶向经典型NF-κB通路的Ibrutinib仅对部分淋巴瘤患者有效。我们的前期研究提示BAFF/MyD88/NIK非经典型NF-κB通路参与Ibrutinib耐药。本项目将分别观察BAFF中和抗体、MyD88抑制剂和NIK/IKKα抑制剂与Ibrutinib的联合作用及其诱导细胞周期阻滞、凋亡和自噬的作用；采用基因测序、Western blot、免疫共沉淀、RNA干扰、ELISA等技术，通过体内外实验发现靶向BAFF/MyD88/NIK非经典型NF-κB通路与Ibrutinib的协同作用机制及预测协同作用的分子标志物，为探索优化非经典型NF-κB通路协同联合经典型NF-κB通路治疗淋巴瘤的新策略打下坚实的基础。

靶向经典型NF-κB 通路的Ibrutinib 仅对部分淋巴瘤患者有效，提示BAFF/MyD88/NIK 非经典型NF-κB 通路参与Ibrutinib 耐药。本项目研究发现：1）在体外细胞水平、体内动物水平以BAFF/MyD88/NIK 非经典型NF-κB 通路为靶点联合BTK 抑制剂Ibrutinib 具有协同抗非霍奇金淋巴瘤的作用；2）探索了预测BTK 抑制剂Ibrutinib 临床疗效的生物标志物，观察以BAFF/MyD88/NIK 非经典型NF-κB通路对BTK抑制剂Ibrutinib的抗B细胞性非霍奇金淋巴瘤作用的影响；3）为将来合理设计临床试验的新方案打下一定基础。探索了基于 BAFF/MyD88/NIK 的非典型NF-κB 通路调控BTK 抑制剂Ibrutinib 的抗淋巴瘤作用及其机制，探索以非经典型NF-κB 通路为靶点联合经典型NF-κB 通路BTK 抑制剂Ibrutinib 协同抗淋巴瘤作用的新策略。