Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics

Area of Science:

• Oncology
• Cancer Metabolism
• Molecular Biology

Background:

• Antiangiogenic therapies are effective against epithelial malignancies but face challenges due to acquired resistance.
• Mutations in MAPK/Pi3K-AKT pathways drive aerobic glycolysis in epithelial tumors, contributing to therapeutic resistance.

Purpose of the Study:

• To investigate the metabolic mechanisms underlying acquired resistance to multikinase inhibitor antiangiogenics (TKIs) in epithelial tumors.
• To identify strategies for overcoming TKI resistance by targeting tumor metabolic pathways.

Main Methods:

• Utilized spontaneous breast and lung tumor models in mice.
• Conducted transcriptomic, metabolomic, and phosphoproteomic analyses to study metabolic shifts.
• Investigated the effects of combining TKIs with agents like phenformin and ME344.

Main Results:

• TKIs induced hypoxia correction in tumors, leading to downregulation of glycolysis and a shift towards mitochondrial respiration.
• This metabolic switch was mediated by HIF1α and AKT downregulation, and AMPK upregulation, enabling fatty acid and ketone body utilization.
• Combined treatment with TKIs and agents like phenformin or ME344 resulted in synergistic tumor control via metabolic synthetic lethality.

Conclusions:

• Tumor resistance to TKIs involves a metabolic shift to mitochondrial respiration, making tumors dependent on this pathway for survival.
• Targeting this metabolic vulnerability, particularly through combination therapies, offers a promising strategy to enhance TKI efficacy and overcome resistance in epithelial cancers.