多发性骨髓瘤(MM)目前仍不可治愈，最主要原因是耐药。一线药物硼替佐米(BTZ)初治疗效显著，但几乎全部复发并获得耐药，即复发难治MM(RRMM)，目前缺乏有效治疗。二代测序排除了靶基因修饰与临床BTZ耐药的关系，BTZ耐药机制不明。我们前期研究发现：凋亡和自噬调节的异常，与BTZ获得性耐药相关，提示信号旁路机制，但其上游途径不清。MM为一种NF-κB依赖性疾病，后者是BTZ的主要靶点，但NF-κB是否参与BTZ耐药，仍属疑问。前期实验显示，NF-κB途径信号分子异常可能参与BTZ耐药的旁路机制。因此，本项目拟进行以下研究：探明BTZ获得性耐药细胞中经典和非经典NF-κB途径的信号分子异常及其临床意义；解析NF-κB通过调节自噬(线粒体自噬)-凋亡交互作用信号网络介导BTZ获得性耐药机制；探索靶向NF-κB介导BTZ耐药分子机制的RRMM治疗策略。为MM精准靶向治疗提供新的思路和策略。

Despite recent significant advances of therapies over the past decade, multiple myeloma (MM) remains incurable, mostly due to drug-resistance. Bortezomib (BTZ) is the first-line treatment, to which patients initially respond well while nearly all patients will eventually relapse (RRMM) and become resistant to standard therapeutic agents. Since genomic sequencing fails to identify any meaningful mutation of the PSMB5 gene in MM patient samples, it suggests an unknown mechanism, other than target modification, accounting for BTZ resistance. Very recently, we have demonstrated that abnormalities in apoptosis and autophagy machinery functionally contribute to acquired BTZ resistance, arguing a signal bypass mechanism. However, the upstream events remain to be defined.MM is an NF-κB-addictive disease, whereas NF-κB is a primary target of BTZ. In this context, our preliminary data showed that NF-κB was constitutively activated in BTZ-resistant MM cells, in association with the alterations in expression of the core signaling molecules, suggesting the involvement of NF-κB in the bypass mechanism for BTZ resistance. To address this hypothesis, here we propose three specific aims: to define abnormalities of both canonical and non-canonical NF-kB pathways in BTZ-resistant MM cells and their clinical significance; to examine whether NF-κB acts to mediate BTZ resistance via regulating the signaling network for cross-talk between apoptosis and autophagy (particularly mitophagy); to exploit the NF-κB-mediated bypass mechanism of BTZ resistance in development of novel precisely targeted strategies for the treatment of RRMM.