ABHD6介导的代谢重编程促进非小细胞肺癌TKI获得性耐药的作用及机制研究

酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）治疗敏感基因突变型非小细胞肺癌在临床上取得了显著效果，但获得性耐药仍是一个普遍且严峻的问题，目前尚无有效解决办法。我们前期研究首次发现ABHD6介导的代谢重编程参与调控TKI获得性耐药，初步探索了其机制，并提出假说：ABHD6抑制葡萄糖摄取负调控糖酵解通路，导致ATP合成下降，诱导能量压力并激活AMPK；激活的AMPK通过PGC1α/ ACC2信号通路，促进脂肪酸的FAO合成ATP，逃逸TKI诱导的能量压力触发的细胞凋亡。本研究拟从肿瘤代谢角度出发，基于代谢组学和转录组学的整合分析发掘TKI获得性耐药的代谢重编程特征，明确ABHD6介导的代谢重编程在TKI获得性耐药中的作用及机制，探索其作为治疗TKI获得性耐药的新靶点。相关原创性发现及深入研究将为临床治疗TKI获得性耐药型肺癌提供新靶点及理论依据。

Tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical results in the treatment of non-small cell lung cancer with corresponding sensitive gene mutations. However, TKI acquired resistance is still a common and serious problem, and there is no effective solutions. In our previous studies, we discovered that ABHD6-mediated metabolic reprogramming is involved in the regulation of TKI acquired resistance. Based on these findings, we hypothesize that ABHD6 inhibits glucose uptake to negatively regulate the glycolytic pathway, resulting in decreased ATP synthesis, inducing energy stress and activating AMPK. Activated AMPK promotes FAO synthesis of ATP from fatty acids by the PGC1α/ACC2 signaling pathway, further escaping apoptosis triggered by energy stress induced by TKIs. In this study, we intend to explore the metabolic reprogramming characteristics of TKI acquired resistance based on integrated analysis of metabolomics and transcriptomics from the perspective of tumor metabolism, and clarify the role and mechanism of ABHD6-mediated metabolic reprogramming in TKI acquired resistance. We expect that the proposed studies will provide new insights into molecular mechanisms that underlie therapy resistance to TKIs and identify rationale-based combination therapies to overcome TKI acquired resistance for patients with non small cell lung cancers.