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Mitochondrial Morphology Dynamics Remodel Metabolism and Affect TKI Sensitivity in EGFR-Mutated Lung Cancer

Yu Zhao1,2,3, Yuqiang Liu2,3, Mingxuan Xie1

  • 1Department of Thoracic Surgery, Sheng Jing Hospital, China Medical University, Shenyang, Liaoning, China.

Cancer Science
|August 13, 2026
PubMed

Insights

EGFR-mutant lung cancer cells develop TKI resistance via mitochondrial metabolic changes. Inhibiting mitochondrial fission and oxidative phosphorylation resensitizes tumors to TKI therapy, offering new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolism

Background:

  • Epidermal Growth Factor Receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) frequently develops resistance to Tyrosine Kinase Inhibitor (TKI) therapy.
  • This TKI resistance is a significant obstacle in effective cancer treatment, potentially linked to tumor cell metabolic reprogramming.

Purpose of the Study:

  • To investigate the cellular and molecular mechanisms underlying TKI resistance in EGFR-mutant lung cancer.
  • To explore the role of mitochondrial dynamics and metabolic reprogramming in TKI resistance.

Main Methods:

  • Established an EGFR-mutant lung cancer mouse model and cultured primary tumor cells.
  • Utilized super-resolution microscopy and RNA-sequencing to analyze mitochondrial morphology.
  • Assessed the effects of inhibiting mitochondrial fission and disrupting oxidative phosphorylation on TKI sensitivity.

Main Results:

  • TKI treatment induced mitochondrial dynamics remodeling toward increased mitochondrial fission in tumor cells.
  • Pharmacological inhibition of mitochondrial fission enhanced tumor cell sensitivity to EGFR-TKIs.
  • Disrupting oxidative phosphorylation (OXPHOS) reversed TKI resistance and increased tumor cell sensitivity.

Conclusions:

  • Mitochondrial OXPHOS metabolic reprogramming mediates energy stress adaptation in tumor cells, influencing TKI treatment response.
  • Targeting mitochondrial metabolism, specifically OXPHOS and fission, presents a promising therapeutic strategy to overcome EGFR-TKI resistance in NSCLC.
Keywords:
EGFR‐mutated non‐small cell lung cancerTKI treatmentcombination therapymitochondrial fissionoxidative phosphorylation

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