Mitochondrial translocation of MDM2 and TFAM reprograms metabolism in treatment-refractory cancers PMID: 41991605

ADC Targets in Oncology

2026-04-10

Mitochondrial translocation of MDM2 and TFAM reprograms metabolism in treatment-refractory cancers

NPJ Precis Oncol. 2026 Apr 16. doi: 10.1038/s41698-025-01257-1.

Jie Qing Eu ¹ ² , Nur Afiqah Binte Mohamed Salleh ² , Jayshree Hirpara ² , Naoto Ohi ³ , Emiri Omori Takaki ³ , Tuan Zea Tan ² , Ju Ee Seet ⁴ , Susan Swee-Shan Hue ⁴ ⁵ ⁶ , Shu Jun Chan ⁵ ⁷ ⁸ , Dorothy Xi Yue Lim ⁹ , Lingzhi Wang ² ¹⁰ , Regina Tong Xin Wong ² , Azhar Ali ² , Yaw Chyn Lim ² ⁵ , Boon-Cher Goh ² ⁷ ⁸ ¹⁰ , Li Ren Kong ¹¹ ¹² ¹³ , Shazib Pervaiz ¹⁴ ¹⁵ ¹⁶ ¹⁷ , Andrea LA Wong ¹⁸ ¹⁹ ²⁰ ²¹

Affiliations

1. Cancer Discovery and Regenerative Medicine Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
2. Cancer Science Institute of Singapore, Singapore, Singapore.
3. Oncology Laboratory, Osaka Research Centre for Drug Discovery, Otsuka Pharmaceutical Co., Ltd, Singapore, Singapore.
4. Department of Pathology, National University of Singapore, Singapore, Singapore.
5. National University Cancer Institute, National University Health System, Singapore, Singapore.
6. Department of Pathology, National University Hospital, Singapore, Singapore.
7. Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
8. Haematology-Oncology Research Group, National University Cancer Institute, Singapore, Singapore.
9. Clinical Trials Unit, Clinical Research & Innovation Office (CRIO), Tan Tock Seng Hospital, Singapore, Singapore.
10. Department of Pharmacology, National University of Singapore, Singapore, Singapore.
11. Cancer Discovery and Regenerative Medicine Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. [email protected].
12. Cancer Science Institute of Singapore, Singapore, Singapore. [email protected].
13. National University Cancer Institute, National University Health System, Singapore, Singapore. [email protected].
14. National University Cancer Institute, National University Health System, Singapore, Singapore. [email protected].
15. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
16. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
17. Integrative Science Program, NUS Graduate School, Singapore, Singapore. [email protected].
18. National University Cancer Institute, National University Health System, Singapore, Singapore. [email protected].
19. Department of Haematology-Oncology, National University Health System, Singapore, Singapore. [email protected].
20. Haematology-Oncology Research Group, National University Cancer Institute, Singapore, Singapore. [email protected].
21. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].

Abstract

Tyrosine kinase inhibitors (TKI) are frontline therapies for oncogene-addicted cancers, yet metabolic rewiring frequently drives acquired resistance. Here, we identify a mitochondrial trafficking mechanism that regulates Oxidative Phosphorylation (OXPHOS) dependence in TKI-resistant tumours. Using resistant cell models and patient-derived Materials, we demonstrate that OXPHOS activation is regulated by an AKT-driven, competitive interaction between mitochondrial MDM2 and the mitochondrial transcription factor TFAM at mitochondrial DNA (mtDNA). Mechanistically, adaptive Akt activation promotes cytosolic redistribution of MDM2 with reciprocal accumulation of TFAM in mitochondrial, enhancing mtDNA transcription and OXPHOS activity. To validate this mitochondrial-cytosolic exchange, we develop a quantitative, high-resolution imaging approach to map MDM2 and TFAM localization. In a TKI-resistant clinical cohort (n = 76), we revealed a positive correlation between Akt activation, MDM2 phosphorylation and TFAM mitochondrial trafficking, defining a spatial, subcellular biomarker signature of metabolically reprogrammed TKI resistance. Pharmacologic disruption of the AKT-MDM2-TFAM signaling axis reverse TKI resistance, linking mitochondrial genome regulation to therapy resistance and suggesting a metabolic vulnerability for combinatorial targeting.