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Purpose of Review <p>This review examines the mechanisms of acquired resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). While genetic bypass mutations are well-understood, the focus here is on lineage plasticity—a non-genetic process where cancer cells evade treatment by altering their cellular identity. The review aims to synthesize how drug-tolerant persister (DTP) cells utilize epigenetic and transcriptomic reprogramming to survive initial therapy, ultimately leading to a phenotypic continuum that ranges from epithelial-mesenchymal transition (EMT) to full histological transformation (e.g., adenocarcinoma to small cell lung cancer).</p> Recent Findings <p>Advances in single-cell transcriptomics (ScRNA-seq) are decoding cancer cell evasion dynamics, revealing key insights: RNA velocity analysis quantifies resistance velocity, predicting future cell-state trajectories beyond static biopsies; master regulons SOX2, SNAI2, and ASCL1 drive cellular plasticity; and mapping trajectories during minimal residual disease (MRD) uncovers vulnerabilities before clinical relapse, enabling targeted interventions.</p> Summary <p>Lineage plasticity is a prevalent but underrecognized hurdle in treating NSCLC. By leveraging computational tools like RNA velocity and GRN inference, clinicians can better predict therapeutic escape routes. This framework supports a shift toward personalized medicine where early interventions, such as combining TKIs with epigenetic modifiers, target master regulators to disrupt plasticity. Such strategies may prevent histological transformation, optimize the timing of clinical trials, and ultimately reduce the risk of recurrence.</p>

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Unraveling the Great Escape: Kinetic Insights into Lineage Plasticity-Driven Resistance in EGFR-Mutant Non-Small Cell Lung Cancer

  • 期刊论文

  • 发表日期：

    2026年4月7日

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  • Isaac Johnson Ajeh,
  • Ozhe Sunday Isaac Ikukpla’si,
  • Adedokun Abigail Abiodun

摘要

Purpose of Review

This review examines the mechanisms of acquired resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). While genetic bypass mutations are well-understood, the focus here is on lineage plasticity—a non-genetic process where cancer cells evade treatment by altering their cellular identity. The review aims to synthesize how drug-tolerant persister (DTP) cells utilize epigenetic and transcriptomic reprogramming to survive initial therapy, ultimately leading to a phenotypic continuum that ranges from epithelial-mesenchymal transition (EMT) to full histological transformation (e.g., adenocarcinoma to small cell lung cancer).

Recent Findings

Advances in single-cell transcriptomics (ScRNA-seq) are decoding cancer cell evasion dynamics, revealing key insights: RNA velocity analysis quantifies resistance velocity, predicting future cell-state trajectories beyond static biopsies; master regulons SOX2, SNAI2, and ASCL1 drive cellular plasticity; and mapping trajectories during minimal residual disease (MRD) uncovers vulnerabilities before clinical relapse, enabling targeted interventions.

Summary

Lineage plasticity is a prevalent but underrecognized hurdle in treating NSCLC. By leveraging computational tools like RNA velocity and GRN inference, clinicians can better predict therapeutic escape routes. This framework supports a shift toward personalized medicine where early interventions, such as combining TKIs with epigenetic modifiers, target master regulators to disrupt plasticity. Such strategies may prevent histological transformation, optimize the timing of clinical trials, and ultimately reduce the risk of recurrence.