Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse.
Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse.
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DOI：
10.1172/jci160152
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发表时间：
2022-10-17
影响因子：
15.9
通讯作者：
Hu, Zeping
中科院分区：
文献类型：
--
作者：
Nie, Meng;Chen, Na;Pang, Huanhuan;Jiang, Tao;Jiang, Wei;Tian, Panwen;Yao, LiAng;Chen, Yangzi;DeBerardinis, Ralph J.;Li, Weimin;Yu, Qitao;Zhou, Caicun;Hu, Zeping
尽管一线表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 疗法对于治疗 EGFR 突变型非小细胞肺癌 (NSCLC) 有效，但现在人们了解到，从初始治疗中逃脱的耐药持久细胞 (DTP) 最终会导致耐药性。在这里，通过代谢组学和转录组学的整合，我们发现神经递质乙酰胆碱（ACh）在DTP细胞中特异性积累，并证明EGFR-TKI治疗通过YAP介导提高了ACh生物合成中限速酶胆碱乙酰转移酶（ChAT）的表达。 ACh 生物合成或 ACh 信号传导的遗传和药理学操作可以可预测地调节体外和体内 DTP 形成的程度。引人注目的是，FDA 批准的达非那新药物在药理学上靶向 ACh/M3R 信号传导，可延缓体内肿瘤复发。从机制上讲，上调的 ACh 代谢部分通过 ACh 毒蕈碱受体 3 (M3R) 激活 WNT 信号传导介导药物耐受。重要的是，我们发现 NSCLC 患者中异常的 ACh 代谢在预测 EGFR-TKI 缓解率和无进展生存期中发挥着潜在作用。因此，我们的研究定义了一种治疗策略——靶向 ACh/M3R/WNT 轴——在 NSCLC 治疗中操纵 EGFR TKI 药物耐受性。
Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non–small cell lung cancer (NSCLC), it is now understood that drug-tolerant persister (DTP) cells escaping from initial treatment eventually drives drug resistance. Here, through integration of metabolomics and transcriptomics, we found that the neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells, and demonstrated that treatment with EGFR-TKI heightened the expression of the rate-limiting enzyme choline acetyltransferase (ChAT) in ACh biosynthesis via YAP mediation. Genetic and pharmacological manipulation of ACh biosynthesis or ACh signaling could predictably regulate the extent of DTP formation in vitro and in vivo. Strikingly, pharmacologically targeting ACh/M3R signaling with an FDA-approved drug, darifenacin, retarded tumor relapse in vivo. Mechanistically, upregulated ACh metabolism mediated drug tolerance in part through activating WNT signaling via ACh muscarinic receptor 3 (M3R). Importantly, we showed that aberrant ACh metabolism in patients with NSCLC played a potential role in predicting EGFR-TKI response rate and progression-free survival. Our study therefore defines a therapeutic strategy — targeting the ACh/M3R/WNT axis — for manipulating EGFR TKI drug tolerance in the treatment of NSCLC.