晚期鼻咽癌姑息化疗容易耐药，预后不良。靶向药物高效低毒，是晚期鼻咽癌治疗的新选择(Annals of Oncology)。我们在鼻咽癌前期研究中发现：对于NOTCH1突变型, PI3K/mTOR双重抑制剂具有协同致死效应，而对野生型则无此效应；更进一步预实验证实：PI3K/mTOR双重抑制剂可下调AKT的磷酸化，并级联下调pFOXO3A，后者进一步下调转录因子FOXM1及相关下游靶分子的表达，最终诱导细胞凋亡。本项目拟通过基因编辑、RPPA等技术明确NOTCH1突变时，PI3K/mTOR双重抑制剂下调AKT及FOXO3A磷酸化的机制，鉴定FOXM1转录激活的下游靶分子，结合PDX模型及临床标本检测验证，最终阐明在NOTCH1突变前提下，PI3K/mTOR双重抑制剂通过AKT/FOXO3A/FOXM1途径发挥协同致死效应的机制，探讨其临床转化应用价值，为晚期鼻咽癌靶向药物转化研究提供新思路。

Palliative chemotherapies for advanced nasopharyngeal carcinoma (NPC) are prone to develop resistance, resulting in a poor clinical outcome. Target therapies have high efficacy and low toxicity, becoming a novel and promising therapeutic option for patients with advanced NPC (Annals of Oncology). Our preliminary studies in NPC have found that, for the NOTCH1 mutants, the PI3K / mTOR dual inhibitor have synergistic lethal effects, which hasn’t been observed in NOTCH1 wild type. Moreover, our study confirmed that PI3K / mTOR dual inhibitor could down-regulate the phosphorylation of AKT and set off a signaling cascade that down-regulates the phosphorylation of FOXO3A, which further decreases the transcription factor FOXM1 and related downstream protein targets. Finally the series of biological processes induce cell apoptosis. This project will apply some advanced technics, including gene editing, Reverse Phase Protein Arrays (RPPA), patient-derived xenografts and clinical specimens testing, to disclose the mechanism underlying the synthetic lethality of PI3K / mTOR dual inhibitor to NOTCH1 mutants through the AKT / FOXO3A / FOXM1 pathway, and further highlight its clinical translational application value，to provide new ideas on exploring the translational studies of target treatments for patients with advanced NPC.