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Cell Rep. 2016 Jun 21;15(12):2705-18. doi: 10.1016/j.celrep.2016.05.052. Epub 2016 Jun 9.

Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics.

Author information

1
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
2
Proteomics Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
3
Bioinformatics Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
4
Molecular Imaging Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
5
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
6
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain. Electronic address: mquintela@cnio.es.

Abstract

Epithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how multikinase inhibitor antiangiogenics (TKIs) induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors downregulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic, and phosphoproteomic study revealed that this metabolic switch is mediated by downregulation of HIF1α and AKT and upregulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, leading to metabolic synthetic lethality. Our study uncovers mechanistic insights in the process of tumor resistance to TKIs and may have clinical applicability.

PMID:
27292634
DOI:
10.1016/j.celrep.2016.05.052
[Indexed for MEDLINE]
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