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  • scRNA-seq-Derived Transcriptional State Trajectories in EGFR-Mutant Lung Adenocarcinoma: A Critical Review of Therapy-Induced Convergence toward a Slow-Cycling Persister Phenotype

  • Alireza Pourrahim,1,*
    1. Student Research Committee, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran


  • Introduction: EGFR tyrosine kinase inhibitors (TKIs) produce initial clinical responses in EGFR-mutant lung adenocarcinoma (LUAD), but drug-tolerant persister (DTP) cells survive treatment and drive acquired resistance. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful approach to resolve the transcriptional heterogeneity and state transitions underlying DTP emergence, yet the evidence across studies has not been critically synthesized.
  • Methods: A critical and comprehensive review of PubMed, Scopus, and Web of Science was conducted using keywords including EGFR-mutant lung adenocarcinoma, drug-tolerant persister cells, scRNA-seq, trajectory inference, AXL, YAP/TAZ, and osimertinib resistance. Studies were included if they applied single-cell or spatial transcriptomics to EGFR-mutant LUAD or related models and reported transcriptional states associated with TKI tolerance. Data were synthesized by thematic framework, focusing on trajectory inference methods, persister cell states, regulatory programs, and therapeutic vulnerabilities. No formal meta-analysis was performed.
  • Results: Untreated cells displayed heterogeneous transcriptional states. Following TKI exposure, trajectory inference revealed an early divergence followed by convergence toward a common slow-cycling persister state. This state was characterized by low expression of proliferation markers (MKI67, TOP2A), enrichment for AXL, and CD74 persister-associated genes, and activation of AXL/MAPK, YAP/TAZ pathways. Convergence was reproducible across cell lines and organoids. Regulon analysis nominated FOSL1, JUN transcription factor as a master regulator of the persister state. Persister cells exhibited reversible drug tolerance and re-entered proliferation upon drug withdrawal.
  • Conclusion: scRNA-seq-derived transcriptional trajectories reveal that EGFR TKI therapy drives convergence toward a slow-cycling persister phenotype in EGFR-mutant LUAD, characterized by AXL/CD74 enrichment, AXL/MAPK and YAP/TAZ pathway activation, and FOSL1/JUN regulon activity. This convergence is reproducible across cell lines and patient-derived organoids, suggesting a conserved, non-genetic route to drug tolerance. Because persister cells remain reversible and re-enter proliferation upon drug withdrawal, they represent a reservoir for acquired resistance. Targeting FOSL1/JUN or the AXL/YAP/TAZ axis may prevent DTP emergence and delay or avert resistance to osimertinib. These findings provide a transcriptional state framework for developing combination strategies that eliminate persister cells rather than merely inhibiting proliferation.
  • Keywords: EGFR-mutant lung adenocarcinoma, scRNA-seq, persister cells, trajectory inference

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