肾癌靶向药酪氨酸激酶抑制剂（TKI）耐受是亟待解决的临床难题，但其机制不明。我们前期研究发现压力反应蛋白激酶GCN2参与调控肾癌细胞对TKI的敏感性，且在耐药肾癌细胞中高表达。后续发现GCN2信号能转录激活FGF、VEGF等，且GCN2上调表达的COX2也参与了肾癌细胞耐药性的维持。所以本项目拟提出理论设想：GCN2压力信号通过转录调控和转录后调控多基因的表达，促进癌细胞抵抗TKI的抗肿瘤作用，例如抑制细胞凋亡和重启血管新生等过程，导致肾癌耐药进展。首先，我们拟在体外和体内模型中，确定耐药肾癌中压力信号在抵抗TKI过程中的重要性；然后，解析TKI激活GCN2的具体方式和相关上下游信号通路网络；随后，筛选并验证GCN2调控的靶基因，分别阐述转录调控和转录后调控的具体分子机制；最后，分析调控网络中关键分子的临床意义。本项目有望筛选到TKI敏感性检测指标，并探索耐药肾癌治疗的新策略。

Resistance to tyrosine kinase inhibitor (TKI) is a major challenge for the treatment of renal cancer. However, the mechanisms remain unclear. Our previous study found that stress responsive general control nonderepressible 2 kinase (GCN2) was involved in the regulation of TKI sensitivity and highly expressed in resistant renal cancer cells. Thereafter, we further found that GCN2 signal could promote FGF and VEGF by transcriptional activation. COX2 was also up-regulated by GCN2 and was involved in the maintenance of drug resistance in renal cancer cells. Therefore, we propose that GCN2 can promote cancer cells to resist the anti-tumor effects of TKI through transcriptional regulation and post-transcriptional regulation of polygene expression, such as inhibiting cell apoptosis and reactivating angiogenesis, leading to the development of renal cancer drug resistance. At first, we will determine the importance of stress signals in TKI resistance in vitro and in vivo models. Furthermore, we plan to analyze how TKI activates GCN2 signaling, and the upstream and downstream signal path network. Moreover, target genes regulated by GCN2 were screened and verified, and specific molecular mechanisms of transcriptional regulation and post-transcriptional regulation were elaborated respectively. At last, we will analyze the clinical significance of the key molecules in renal cancer. This project will explore potential predictors and targets for the treatment of TKI resistant renal cancers.