---
title: "Four-gene persister signature and ZLN005-triggered GSDME pyroptosis in EGFR‑mutant lung cancer"
id: "pubmed-42757482"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42757482"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42757482/"
doi: "10.3892/mmr.2026.14017"
published_at: "2026-09-18T12:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Four-gene persister signature and ZLN005-triggered GSDME pyroptosis in EGFR‑mutant lung cancer
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42757482
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42757482/)
- **DOI:** [10.3892/mmr.2026.14017](https://doi.org/10.3892%2Fmmr.2026.14017)
- **Published At:** 2026-09-18T12:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Drug-tolerant persister cells limit durable responses to **EGFR** tyrosine kinase inhibitors in EGFR‑mutant lung adenocarcinoma. - The authors integrated public transcriptomic datasets from cell models treated with EGFR inhibitors and other RTK/RAS/MAPK pathway agents with machine-learning feature selection, survival analysis and Cancer Dependency Map pharmacogenomic screening. - A **four-gene signature** (B-cell translocation gene 1 protein, inhibitor of growth protein 4, proline-rich nuclear receptor coactivator 1, and calcium-binding and coiled-coil domain-containing protein 1) was identified as associated with a targeted therapy–induced persister state and worse patient survival. - Experimental validation in PC‑9 and HCC827 cells showed rapid induction of these genes during **osimertinib** treatment; doxycycline-inducible shRNA knockdown of each gene reduced persister cell formation. - Pharmacogenomic screening nominated **ZLN005**, a PGC‑1α agonist, which synergized with osimertinib to lower persister viability in cell models. - Mechanistic studies indicated ZLN005 enhanced mitochondrial oxidative metabolism and reactive oxygen species, activating caspase‑3 and triggering **GSDME**-associated **pyroptotic** cell death. - Findings map transcriptional and metabolic features of TKI-induced persisters and reveal a metabolic vulnerability exploitable by ZLN005 in EGFR‑mutant lung adenocarcinoma. - Details such as precise dataset identifiers, sample sizes, quantitative effect sizes, in vivo validation, and clinical data were not reported in the abstract and thus are not available from the source provided.
## Clinical Analysis & Structured Key Points
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Epub 2026 Sep 18. # A four‑gene signature identifies TKI‑induced persister cells and uncovers a ZLN005‑induced pyroptotic vulnerability via the GSDME pathway in EGFR‑mutant lung cancer [Wenwen Chang](https://pubmed.ncbi.nlm.nih.gov/?term=Chang+W&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Jiaxin Yuan](https://pubmed.ncbi.nlm.nih.gov/?term=Yuan+J&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Huilin Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+H&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Ying Yu](https://pubmed.ncbi.nlm.nih.gov/?term=Yu+Y&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Yan Ma](https://pubmed.ncbi.nlm.nih.gov/?term=Ma+Y&cauthor_id=42757482)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-2 "Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Mingyue Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+M&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Wenjing Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+W&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Hongxia Yan](https://pubmed.ncbi.nlm.nih.gov/?term=Yan+H&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Chongran Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+C&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Peng Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+P&cauthor_id=42757482)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-3 "Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China."), [Yang Tian](https://pubmed.ncbi.nlm.nih.gov/?term=Tian+Y&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Feng Guo](https://pubmed.ncbi.nlm.nih.gov/?term=Guo+F&cauthor_id=42757482)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-2 "Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Pan Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+P&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Yang Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+Y&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#full-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.") Affiliations Expand ### Affiliations * 1 Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China. * 2 Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China. * 3 Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China. * PMID: **42757482** * DOI: [ 10.3892/mmr.2026.14017 ](https://doi.org/10.3892/mmr.2026.14017) Item in Clipboard # A four‑gene signature identifies TKI‑induced persister cells and uncovers a ZLN005‑induced pyroptotic vulnerability via the GSDME pathway in EGFR‑mutant lung cancer Wenwen Chang et al. Mol Med Rep. 2026 Nov. Show details Display options Display options Format Abstract PubMed PMID Mol Med Rep Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Mol+Med+Rep%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Mol+Med+Rep%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42757482/) . 2026 Nov;34(5):306. doi: 10.3892/mmr.2026.14017. Epub 2026 Sep 18. ### Authors [Wenwen Chang](https://pubmed.ncbi.nlm.nih.gov/?term=Chang+W&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Jiaxin Yuan](https://pubmed.ncbi.nlm.nih.gov/?term=Yuan+J&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Huilin Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+H&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Ying Yu](https://pubmed.ncbi.nlm.nih.gov/?term=Yu+Y&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Yan Ma](https://pubmed.ncbi.nlm.nih.gov/?term=Ma+Y&cauthor_id=42757482)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-2 "Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Mingyue Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+M&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Wenjing Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+W&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Hongxia Yan](https://pubmed.ncbi.nlm.nih.gov/?term=Yan+H&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Chongran Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+C&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Peng Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+P&cauthor_id=42757482)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-3 "Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China."), [Yang Tian](https://pubmed.ncbi.nlm.nih.gov/?term=Tian+Y&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Feng Guo](https://pubmed.ncbi.nlm.nih.gov/?term=Guo+F&cauthor_id=42757482)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-2 "Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Pan Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+P&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China."), [Yang Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+Y&cauthor_id=42757482)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757482/#short-view-affiliation-1 "Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.") ### Affiliations * 1 Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China. * 2 Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China. * 3 Department of Oncology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China. * PMID: **42757482** * DOI: [ 10.3892/mmr.2026.14017 ](https://doi.org/10.3892/mmr.2026.14017) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract Drug‑tolerant persister cells represent a major barrier to durable responses in cases of epidermal growth factor receptor (EGFR)‑mutant lung adenocarcinoma treated with tyrosine kinase inhibitors. To define the molecular features and actionable vulnerabilities of this cell state, public transcriptomic datasets from tumour cell‑based models treated with EGFR inhibitors or other targeted agents within the receptor tyrosine kinase (RTK)/RAS/MAPK pathway were integrated with machine‑learning‑based feature selection, survival analysis and Cancer Dependency Map‑based pharmacogenomic screening. The present study also performed experimental validation of identified genes and drugs in PC‑9 and HCC827 cell models. A four‑gene persister‑associated gene signature comprising B‑cell translocation gene 1 protein, inhibitor of growth protein 4, proline‑rich nuclear receptor coactivator 1 and calcium‑binding and coiled‑coil domain‑containing protein 1 was identified, which defined a targeted therapy‑induced persister state and associated with poor patient survival. Functional validation using reverse transcription‑quantitative PCR, doxycycline‑inducible short hairpin RNA knockdown and β‑galactosidase staining assays demonstrated rapid induction of these genes during osimertinib treatment and showed that depletion of each gene markedly impaired drug‑tolerant persister cell formation. Pharmacogenomic analysis identified ZLN005, a peroxisome proliferator‑activated receptor γ coactivator‑1α agonist, as a candidate metabolic modulator that synergized with osimertinib to reduce persister cell viability. Mechanistically, ZLN005 enhanced mitochondrial oxidative metabolism and reactive oxygen species accumulation, leading to caspase‑3 activation and gasdermin E‑associated pyroptotic cell death. Collectively, these findings defined the transcriptional and metabolic features of targeted therapy‑induced persister cells and revealed a metabolic vulnerability to ZLN005 in EGFR‑mutant lung adenocarcinoma. **Keywords:** EGFR; TKIs; drug‑tolerant persister cells; gasdermin E; lung adenocarcinoma; machine learning; metabolism; osimertinib; peroxisome proliferator‑activated receptor γ coactivator‑1α agonist ZLN005; pyroptosis. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Similar articles * [ IFITM3-MET interaction drives osimertinib resistance through AKT pathway activation in EGFR-mutant non-small cell lung cancer. ](https://pubmed.ncbi.nlm.nih.gov/41152910/) Ibusuki R, Iwama E, Shimauchi A, Kawano H, Mizusaki S, Nakamura S, Miyazaki Y, Inutsuka Y, Hashisako M, Harada T, Tsuchiya-Kawano Y, Tsutsumi H, Nakanishi T, Nakagaki N, Koga Y, Kimura S, Mashimoto S, Shibahara D, Otsubo K, Yoneshima Y, Tanaka K, Oda Y, Okamoto I.Ibusuki R, et al.Mol Cancer. 2025 Oct 28;24(1):272. doi: 10.1186/s12943-025-02493-6.Mol Cancer. 2025.PMID: 41152910Free PMC article. * [ USP7-dependent stabilization of FKBP4 contributes to acquired osimertinib resistance through glycolytic remodeling in NSCLC. ](https://pubmed.ncbi.nlm.nih.gov/42031983/) Pang W, Fang M, Wu W.Pang W, et al.Sci Rep. 2026 Apr 24;16(1):18984. doi: 10.1038/s41598-026-49053-6.Sci Rep. 2026.PMID: 42031983Free PMC article. * [ EGFR-TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer. ](https://pubmed.ncbi.nlm.nih.gov/40479551/) Zhang Y, Zhang X, Yang X, Chen X, Wang Y, Hu J, Liu R, Luo X.Zhang Y, et al.Adv Sci (Weinh). 2025 Aug;12(31):e06950. doi: 10.1002/advs.202506950. Epub 2025 Jun 6.Adv Sci (Weinh). 2025.PMID: 40479551Free PMC article. * [ Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma. ](https://pubmed.ncbi.nlm.nih.gov/33435596/) Rybarczyk-Kasiuchnicz A, Ramlau R, Stencel K.Rybarczyk-Kasiuchnicz A, et al.Int J Mol Sci. 2021 Jan 8;22(2):593. doi: 10.3390/ijms22020593.Int J Mol Sci. 2021.PMID: 33435596Free PMC article.Review. * [ Strategies of overcoming osimertinib resistance in EGFR-mutated non-small cell lung cancer. ](https://pubmed.ncbi.nlm.nih.gov/40853210/) Jiang Q, Jin Y, Wang W, Chen Y, Tian L, Wang X, Wu A, Tian R, Pan J, Gong Y.Jiang Q, et al.J Drug Target. 2026 Mar;34(3):358-371. doi: 10.1080/1061186X.2025.2552431. Epub 2025 Sep 1.J Drug Target. 2026.PMID: 40853210Review. [ See all similar art
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