Scholarlink

<p>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 (<i>n</i> = 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月16日

查看全文
  • Jie Qing Eu,
  • Nur Afiqah Binte Mohamed Salleh,
  • Jayshree Hirpara,
  • Naoto Ohi,
  • Emiri Omori Takaki,
  • Tuan Zea Tan,
  • Ju Ee Seet,
  • Susan Swee-Shan Hue,
  • Shu Jun Chan,
  • Dorothy Xi Yue Lim,
  • Lingzhi Wang,
  • Regina Tong Xin Wong,
  • Azhar Ali,
  • Yaw Chyn Lim,
  • Boon-Cher Goh,
  • Li Ren Kong,
  • Shazib Pervaiz,
  • Andrea LA Wong

摘要

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.