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Peer-reviewedCC BY-NC-NDCellular oncology (Dordrecht, Netherlands)

Genomic landscape of EGFR-TKI resistance: from known mechanisms to unknown resistance.

  • Songchen Zhao1,2
  • Fei Zhou2
  • Wenshuai Chen3
  • Shuchun Wang4
  • Caicun Zhou5,6
6 affiliations
  1. 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
  2. 2Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
  3. 3Geneplus-Beijing, Beijing, 102206, China.
  4. 4Geneplus-Beijing, Beijing, 102206, China. [email protected].
  5. 5Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].
  6. 6Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].
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Abstract

Purpose

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) serve as the standard first-line therapy for advanced EGFR-mutant non-small-cell lung cancer (NSCLC). However, resistance inevitably restricts their efficacy. Although well-documented acquired resistance mechanisms have been extensively characterized, approximately 30% of patients with EGFR-TKI resistance still present with unknown resistance (UR) mechanisms, and the driving factors behind primary resistance remain inadequately understood.Methods

In this study, we conducted a large-scale, retrospective cohort study, performing target-capture deep sequencing (>400 genes) on 928 samples from 745 EGFR-TKI-resistant and 183 TKI-naïve EGFR-mutant NSCLC patients.Results

The molecular landscape of EGFR-TKI resistance was systematically characterized. In the resistance cohort, 68.72% (512/745) harbored known resistance (KR) mechanisms, while 31.28% (233/745) were classified as UR. The landscape of KR was significantly influenced by EGFR-TKI generation. First-line third-generation TKI resistance demonstrated fewer EGFR-dependent events compared to first-generation TKIs (p < 0.01) and more RTK and PI3K-AKT-mTOR (PAM) pathway alterations (p < 0.05). In the UR cohort, pathway analysis revealed unique enrichment of atypical pathways, most notably ATP-dependent chromatin remodeling pathways. Differential gene analysis identified significant enrichment of MYC, BRCA1, EPHB, and PTPRD in the UR subgroup. To investigate primary resistance, we found that baseline IKZF1 amplification was significantly enriched in patients with short time-to-treatment-failure (TTF) and correlated with significantly poorer outcomes (HR = 3.02, 95% CI 1.32-6.90; log-rank p = 0.004).Conclusions

This study provides a comprehensive real-world landscape of EGFR-TKI resistance, demonstrating distinct mechanisms influenced by TKI generation. ATP-dependent chromatin remodeling was identified as a distinctive pathway feature of unknown resistance, and baseline IKZF1 amplification emerged as a candidate biomarker of EGFR-TKI primary resistance. These findings suggest that epigenetic dysregulation may be a critical driver of both unknown and primary resistance to EGFR-TKIs.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026genomic,
  title = {{Genomic landscape of EGFR-TKI resistance: from known mechanisms to unknown resistance.}},
  author = {Songchen Zhao and Fei Zhou and Wenshuai Chen and Shuchun Wang and Caicun Zhou},
  journal = {Cellular oncology (Dordrecht, Netherlands)},
  year = {2026},
  month = aug,
  doi = {10.1007/s13402-026-01253-y},
  url = {https://europepmc.org/article/MED/42957912},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Genomic landscape of EGFR-TKI resistance: from known mechanisms to unknown resistance.
AU  - Songchen Zhao
AU  - Fei Zhou
AU  - Wenshuai Chen
AU  - Shuchun Wang
AU  - Caicun Zhou
PY  - 2026
DA  - 2026/08/04
JO  - Cellular oncology (Dordrecht, Netherlands)
DO  - 10.1007/s13402-026-01253-y
UR  - https://europepmc.org/article/MED/42957912
AB  - Purpose  Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) serve as the standard first-line therapy for advanced EGFR-mutant non-small-cell lung cancer (NSCLC). However, resistance inevitably restricts their efficacy. Although well-documented acquired resistance mechanisms have been extensively characterized, approximately 30% of patients with EGFR-TKI resistance still present with unknown resistance (UR) mechanisms, and the driving factors behind primary resistance remain inadequately understood.Methods  In this study, we conducted a large-scale, retrospective cohort study, performing target-capture deep sequencing (>400 genes) on 928 samples from 745 EGFR-TKI-resistant and 183 TKI-naïve EGFR-mutant NSCLC patients.Results  The molecular landscape of EGFR-TKI resistance was systematically characterized. In the resistance cohort, 68.72% (512/745) harbored known resistance (KR) mechanisms, while 31.28% (233/745) were classified as UR. The landscape of KR was significantly influenced by EGFR-TKI generation. First-line third-generation TKI resistance demonstrated fewer EGFR-dependent events compared to first-generation TKIs (p < 0.01) and more RTK and PI3K-AKT-mTOR (PAM) pathway alterations (p < 0.05). In the UR cohort, pathway analysis revealed unique enrichment of atypical pathways, most notably ATP-dependent chromatin remodeling pathways. Differential gene analysis identified significant enrichment of MYC, BRCA1, EPHB, and PTPRD in the UR subgroup. To investigate primary resistance, we found that baseline IKZF1 amplification was significantly enriched in patients with short time-to-treatment-failure (TTF) and correlated with significantly poorer outcomes (HR = 3.02, 95% CI 1.32-6.90; log-rank p = 0.004).Conclusions  This study provides a comprehensive real-world landscape of EGFR-TKI resistance, demonstrating distinct mechanisms influenced by TKI generation. ATP-dependent chromatin remodeling was identified as a distinctive pathway feature of unknown resistance, and baseline IKZF1 amplification emerged as a candidate biomarker of EGFR-TKI primary resistance. These findings suggest that epigenetic dysregulation may be a critical driver of both unknown and primary resistance to EGFR-TKIs.
SN  - 2211-3428
SN  - 2211-3436
ER  -