复发是鼻咽癌治疗失败根源之一，但其机制未明。筛选和鉴定驱动鼻咽癌复发的基因突变，是揭示鼻咽癌复发机制，找到特异性靶标的关键。申请人前期对复发-原发鼻咽癌配对样本行高通量测序及生物信息学分析发现NF-κB通路基因的主克隆突变与鼻咽癌复发密切相关。通过体内体外实验发现NF-κB通路基因的突变增强NF-κB通路活性，并提高鼻咽癌细胞的干性。因此，我们提出如下科学假说，基因突变激活NF-κB通路活性并促进鼻咽癌复发。本项目拟通过小分子抑制剂、CRISPR-CAS9技术，荷瘤小鼠模型阐明基因突变能否增强NF-κB通路活性从而增强鼻咽癌细胞的干性，基因突变激活NF-κB通路活性的机制，并建立基于NF-κB通路活性的临床预后预测模型。通过本项目，不但能完善NF-κB通路基因突变在鼻咽癌复发中的作用及机制，也为鼻咽癌复发的风险分层及精准治疗提供依据。

Local recurrence is one of the main causes of treatment failure in nasopharyngeal carcinoma (NPC), but its mechanism remains unknown. Screening and identifying the key gene mutations which promote the recurrence of NPC is the key to revealing the mechanism of local recurrence in NPC and finding specific targets. The applicant previously conducted high-throughput sequencing and bio-informatics analysis of the paired recurrent-primary NPC samples and found that the clonal mutations of NF-κB pathway genes were closely related to the recurrence of NPC. Furthermore, in vitro and in vivo experiments have revealed that gene mutations enhanced the NF-κB pathway activity and increased the stemness of NPC cells. Therefore, we proposed the following scientific hypothesis that the gene mutations activate NF-κB pathway to promote the recurrence of NPC. We intend to utlize small molecule inhibitors, CRISPR-CAS9 technology, tumor-bearing mouse models to clarify whether the gene mutations could activate NF-κB pathway, thereby enhancing the stemness of NPC cells, the mechanism of gene mutations activating NF-κB pathway and to establish a clinical prognostic prediction model based on NF-κB pathway activity. This project will not only clarify the role and mechanism of NF-κB pathway gene muations in NPC recurrence, but also provide new ideas for risk stratification and individualized treatment of NPC recurrence.