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Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
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Mitochondrial translocation of MDM2 and TFAM reprograms metabolism in treatment-refractory cancers

Jie Qing Eu1,2, Nur Afiqah Binte Mohamed Salleh2, Jayshree Hirpara2

  • 1Cancer Discovery and Regenerative Medicine Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.

NPJ Precision Oncology
|April 16, 2026
PubMed

Insights

Metabolic rewiring drives cancer therapy resistance. This study reveals how AKT signaling controls mitochondrial protein trafficking, impacting oxidative phosphorylation and TKI resistance, offering new therapeutic targets.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Metabolic Regulation

Background:

  • Tyrosine kinase inhibitors (TKIs) are crucial for oncogene-addicted cancers.
  • Metabolic reprogramming is a common mechanism of acquired resistance to TKIs.
  • Understanding resistance mechanisms is vital for improving cancer therapy.

Purpose of the Study:

  • To identify mechanisms regulating metabolic rewiring in TKI-resistant cancers.
  • To elucidate the role of mitochondrial trafficking in oxidative phosphorylation (OXPHOS) dependence.
  • To explore the AKT-MDM2-TFAM axis as a potential therapeutic target.

Main Methods:

  • Utilized resistant cancer cell models and patient-derived materials.
  • Developed a quantitative, high-resolution imaging approach to map protein localization.
  • Analyzed a clinical cohort (n=76) of TKI-resistant patients.

Main Results:

  • Identified an AKT-driven mechanism involving MDM2 and TFAM mitochondrial trafficking.
  • Demonstrated that AKT activation promotes MDM2 cytosolic shift and TFAM mitochondrial accumulation.
  • Observed a correlation between AKT activation, MDM2 phosphorylation, TFAM trafficking, and TKI resistance in patients.
  • Showed that disrupting the AKT-MDM2-TFAM axis reverses TKI resistance.

Conclusions:

  • Mitochondrial trafficking regulates OXPHOS and TKI resistance.
  • The AKT-MDM2-TFAM axis serves as a biomarker for metabolic reprogramming in TKI resistance.
  • Targeting this axis offers a metabolic vulnerability for combinatorial cancer therapy.

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