ArticleThe Journal of clinical investigation2022
Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 72 citations in OpenAlex.
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- Neurotransmitter receptor-associated gene signature: prognostic and immunosuppressive microenvironment in NSCLC.Future science OA · 2026Article
- Neural regulation in lung cancer: from mechanisms to new therapeutic perspectives.Clinical and experimental medicine · 2026Review
- Metabolic pathways and chemotherapy resistance in acute myeloid leukemia (AML): Insights into Enoyl-CoA hydratase domain-containing protein 3 (Cancer pathogenesis and therapy · 2026Article
- NPC2 suppresses osteolytic metastasis in lung adenocarcinoma via the AKT/mTOR pathway and tumor-osteoclast crosstalk.iScience · 2026Article
- Neuro-tumor interactions in peripheral tumors.Cancer metastasis reviews · 2026Review
- The landscape of B and plasma cells in breast cancer: insights from single-cell and spatial transcriptomics.NPJ breast cancer · 2026Article
- Transfer of Damaged Mitochondria from Cancer Cells to Cancer-Associated Fibroblasts Promotes Tyrosine Kinase Inhibitor Tolerance in EGFR-Mutant Lung Cancer.Cancer research · 2026Article
- Established and Emerging Therapies for High-Risk Neuroblastoma.Paediatric drugs · 2026Review
- Inhibition of GALNT7 suppresses cell proliferation and invasiveness while elevating cell apoptosis via the inactivation of the AKT pathway in non-small cell lung cancer.BMJ open respiratory research · 2026Article
- Bidirectional crosstalk between the nervous system and the tumour microenvironment: mechanisms, feedback loops and therapeutic opportunities.Frontiers in cell and developmental biology · 2026Review
- Mitochondrial niches of residual disease in EGFR-mutant NSCLC: immune-constrained persistence and therapeutic interception.Frontiers in immunology · 2026Review
- Neural regulation of lung cancer: from mechanisms to clinical implications.European journal of medical research · 2025Review
- Harnessing multi-omics approaches to decipher tumor evolution and improve diagnosis and therapy in lung cancer.Biomarker research · 2025Review
- Eradicating Drug-tolerant Persister Cells in EGFR-Mutated Non-Small Cell Lung Cancer by Targeting TROP2 with CAR-T Cellular Therapy.Cancer discovery · 2025Article
- Neurotransmitter Regulatory Networks: A New Perspective on Cancer Therapy.Biomolecules · 2025Review
- The role of acetylcholine and its receptors in tumor immune regulation: mechanisms and potential therapeutic targets.Molecular cancer · 2025Review
- Neurotransmitters: an emerging target for therapeutic resistance to tumor immune checkpoint inhibitors.Molecular cancer · 2025Review
- Integrating neuroscience and oncology: neuroimmune crosstalk in the initiation and progression of digestive system tumors.Molecular cancer · 2025Review
- EGFR-TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.