RAD001联合PD-1抑制剂阻遏eIF4E磷酸化增效鼻咽癌治疗的分子机制研究

15%-30%的中晚期鼻咽癌患者放化疗后出现远处转移和/或复发。磷酸化eIF4E促进肿瘤恶性进展。肿瘤细胞内源性PD-1磷酸化eIF4E。我们前期发现mTOR抑制剂RAD001诱导eIF4E磷酸化，RAD001联合PD-1抗体诱导凋亡，显著抑制鼻咽癌细胞增殖。据此提出如下科学假说：RAD001在治疗鼻咽癌过程中依赖于肿瘤细胞内源性PD-1与PD-L1的结合诱导eIF4E磷酸化，PD-1激活后经桥梁RPTOR与eIF4E形成三元复合体，引起eIF4E的磷酸化，增加鼻咽癌干性，促进鼻咽癌细胞异常增殖，导致鼻咽癌对RAD001产生耐药，降低其疗效；RAD001联合PD-1抗体阻遏eIF4E磷酸化，以不依赖免疫效应机制协同增效治疗鼻咽癌。本项目拟从鼻咽癌组织、细胞和动物模型三个层次四个方面的研究，阐明RAD001联合PD-1抗体增效鼻咽癌治疗的具体分子机制，为鼻咽癌综合治疗提供新的策略和理论依据。

There are 15% to 30% of patients with moderated and advanced-stage nasopharyngeal carcinoma (NPC) developing distant metastasis and/or recurrence after treatment with radiochemical therapy. The phosphorylated eIF4E plays a key role in the malignant progression of tumors. The intrinsic PD-1(programmed cell death protein 1) of tumor cells activated eIF4E phosphorylation directly. Our previous data showed the negative feedback of mTOR inhibitor RAD001 activated eIF4E phosphorylation. Combination RAD001 and anti-PD-1 can significantly induce apoptosis, decrease proliferation of NPC cells. Basing on the results above, we put forward the hypothesis that RAD001 relies on the interaction between PD-1 and its ligand PD-L1 to induce eIF4E phosphorylation. After PD-1 activation, the bridge RPTOR and eIF4E form a ternary complex, which induces eIF4E phosphorylation, enhances the stemness of NPC, promotes cell aberrant proliferation, then resulting the RAD001 resistance of therapy of NPC; Combination of RAD001 and PD-1 antibody inhibits eIF4E phosphorylation will synergistically enhance the treatment efficacy of NPC independently of adaptive immunity. This project aims to elucidate the specific molecular mechanism on combination of RAD001 and PD-1 antibody in the treatment of NPC from three different levels and exploring the four different aspects using clinical specimens of human NPC, cell lines and animal models. The achievement of research project will provide a new strategy and theoretical basis for clinical transformation of comprehensive treatment of NPC.