ENPP1介导的嘧啶代谢重编程在EGFR TKI耐药中的作用及机制研究

分子靶向药物EGFR TKI的“脱靶”耐药性是非小细胞肺癌（NSCLC）治疗的重要挑战，仍需探寻其他层面的新机制。代谢异常为肿瘤耐药性的重要机制之一，但目前NSCLC对TKI耐药的代谢机制尚不清楚。我们前期的代谢组学和转录组学研究发现，耐药NSCLC细胞中的嘧啶回补途径及其关键酶ENPP1显著上调；而干预该通路的关键酶ENPP1可显著逆转耐药性，提示嘧啶代谢重编程参与NSCLC对TKI耐药的发生及调控。本项目拟在细胞株和裸鼠移植瘤耐药模型中，利用代谢组学和新型代谢流分析，整合转录组学和细胞/分子生物学等技术，明确嘧啶回补代谢途径及其关键酶ENPP1在耐药中的功能；探讨靶向干预该通路关键酶ENPP1以逆转耐药性的可行性；并阐明该代谢通路的上下游分子调控机制。本项目将从代谢层面深入揭示EGFR TKI耐药的分子机制，并发现和验证逆转耐药性的新靶点，为临床提供克服TKI耐药性的新思路和新策略。

The "off-target" resistance to targeted therapy drug EGFR TKI is a critical challenge in the treatment of non-small cell lung cancer (NSCLC), and new mechanisms from other perspective are still needed. Metabolic perturbation is one of the important mechanisms of tumor drug resistance, but the metabolic mechanism of NSCLC resistance to TKI is still unclear. Our previous metabolomics and transcriptomics studies showed that the pyrimidine-salvage pathway and its key enzyme ENPP1 in drug-resistant NSCLC cells were significantly up-regulated; while intervention of the key enzyme ENPP1 significantly reversed drug resistance, suggesting that reprogramming of pyrimidine metabolism plays a critical role in occurrence and regulation of TKI resistance in NSCLC. This project aims to utilize metabolomics and novel metabolic flux analysis, together with transcriptomics and cell/molecular biology techniques: to identify the function of the pyrimidine-salvage pathway and its key enzyme ENPP1 in cell model and nude mouse xenograft models; to explore the feasibility to reverse drug resistance by targeting the key enzyme ENPP1; and elucidate the upstream and downstream molecular regulation mechanisms of this metabolic pathway. This project will reveal the molecular mechanism of EGFR TKI resistance from the metabolic perspective, and identify and validate new targets for TKI resistance, and provide new ideas and strategies for overcoming TKI drug resistance.