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Lineage Plasticity and Histologic Transformation in EGFR-TKI Resistant Lung Cancer.

Li Yieng Eunice Lau1,2, Anders Jacobsen Skanderup1, Aaron C Tan3,4

  • 1Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore.

International Journal of Molecular Sciences
|January 10, 2026
PubMed
Summary

Lineage plasticity allows cancer cells to resist therapies by changing their type, notably in EGFR-mutant lung adenocarcinoma. Understanding this transformation is key to developing new treatments.

Keywords:
EGFR-TKIacquired resistanceepigenetic reprogramminghistologic transformationlineage plasticitylung adenocarcinomalung cancertargeted therapytranscriptional reprogramming

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Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Medicine

Background:

  • Lineage plasticity, the adaptive reprogramming of cancer cells, is a significant cause of therapeutic resistance.
  • In EGFR-mutant lung adenocarcinoma (LUAD), this plasticity often leads to histologic transformation into small-cell lung cancer (SCLC), a major resistance mechanism against tyrosine kinase inhibitors (TKIs).
  • Transformed tumors retain the EGFR mutation but become EGFR-independent, exhibiting aggressive behavior and poor outcomes.

Purpose of the Study:

  • To explore the mechanisms and implications of lineage plasticity in EGFR-mutant LUAD.
  • To investigate how cancer cells acquire resistance through phenotypic and histological changes.
  • To identify potential therapeutic vulnerabilities associated with lineage plasticity.

Main Methods:

  • Review of recent genomic, transcriptomic, and epigenetic studies on lineage plasticity.
  • Analysis of spatial and single-cell profiling data to understand tumor heterogeneity.
  • Utilizing functional models and multi-omics approaches to identify therapeutic targets.

Main Results:

  • Lineage plasticity, including histologic transformation to SCLC, is a prevalent resistance mechanism in EGFR-mutant LUAD.
  • Molecular alterations often precede overt histological changes, indicating early reprogramming.
  • Heterogeneous trajectories and intermediate states are observed, suggesting complex adaptive pathways.
  • Therapeutic vulnerabilities distinct from de novo SCLC and classical LUAD are being identified.

Conclusions:

  • Lineage plasticity is a critical challenge in treating EGFR-mutant LUAD, driving resistance to TKIs.
  • Understanding the molecular basis and temporal dynamics of plasticity is essential for early detection and targeted therapies.
  • Developing novel therapeutic strategies that address plasticity-driven resistance is crucial for improving patient outcomes.