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Updated: Apr 28, 2026

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From EGFR PTM network to TKI resistance: spatial subtypes and targeting in lung cancer

Birou Lai1,2, Chang Xu3, Siyi Lai3

  • 1The First Affiliated Hospital of Henan Medical University, Xinxiang 453100, Henan, China.

Cancer Drug Resistance (Alhambra, Calif.)
|April 27, 2026
PubMed

Insights

Resistance to lung cancer treatments like EGFR inhibitors is a major hurdle. This review explores how EGFR’s post-translational modifications (PTMs) drive resistance, proposing new subtypes and targeting strategies beyond simple inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Lung cancer is a leading cause of cancer death globally.
  • Epidermal growth factor receptor (EGFR) inhibitors are effective but face resistance.
  • Post-translational modifications (PTMs) of EGFR are crucial for its function and regulation.

Purpose of the Study:

  • To comprehensively review the role of six key EGFR PTMs in resistance.
  • To propose a novel classification of EGFR resistance subtypes based on PTMs and localization.
  • To identify new therapeutic strategies targeting PTM networks.

Main Methods:

  • Literature review of EGFR signaling and PTMs.
  • Mechanistic analysis of PTM interplay and spatial localization.
  • Framework development for resistance classification and therapeutic targeting.

Main Results:

  • Six key PTMs (phosphorylation, palmitoylation, ubiquitination, glycosylation, acetylation, S-nitrosylation) significantly influence EGFR signaling, turnover, and trafficking.
  • A novel classification of resistance subtypes is proposed: membrane-retained, degradation-evading, nuclear-localized, and mitochondrial-localized EGFR.
  • Complex crosstalk among PTMs dictates EGFR fate and function, with specific PTM hubs and networks identified.

Conclusions:

  • Targeting specific PTM hubs or networks, not just EGFR, is a promising strategy to overcome resistance.
  • Integrating multi-PTM profiling with spatial proteomics is essential for precision combination therapies.
  • Reprogramming the pathological PTM network offers a paradigm shift for treating resistant lung cancer.
Keywords:
EGFRLung cancerTKI resistancedegradationspatial PTMsubcellular trafficking

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