TY - JOUR
T1 - Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse
AU - Nie, Meng
AU - Chen, Na
AU - Pang, Huanhuan
AU - Jiang, Tao
AU - Jiang, Wei
AU - Tian, Panwen
AU - Yao, Li Ang
AU - Chen, Yangzi
AU - DeBerardinis, Ralph J.
AU - Li, Weimin
AU - Yu, Qitao
AU - Zhou, Caicun
AU - Hu, Zeping
N1 - Funding Information:
We thank members of the Hu laboratory for critiquing the manuscript. We thank the West China Biobanks, Department of Clinical Research Management, West China Hospital of Sichuan University for provision of biospecimens. ZH is supported by grants from the National Key R&D Program of China (2020YFA0803300), National Natural Science Foundation of China (81973355 and 92057209), National Science and Technology Major Project for “Significant New Drugs Development” (2017ZX09304015), Agilent Applications and Core Technology University Research (ACT-UR) grant (Research Gift 4214), Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, and Boehringer-Ingelheim (China).
Publisher Copyright:
Copyright: © 2022, Nie et al.
PY - 2022/10/17
Y1 - 2022/10/17
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI160152
DO - 10.1172/JCI160152
M3 - Article
C2 - 36048538
AN - SCOPUS:85140144063
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 20
M1 - e160152
ER -