Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics

Paloma Navarro, Maria J. Bueno, Ivana Zagorac, Tamara Mondejar, Jesus Sanchez, Silvana Mourón, Javier Muñoz, Gonzalo Gómez-López, Veronica Jimenez-Renard, Francisca Mulero, Navdeep S. Chandel, Miguel Quintela-Fandino*

*Corresponding author for this work

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2705-2718
Number of pages14
JournalCell reports
Volume15
Issue number12
DOIs
StatePublished - Jun 21 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Navarro, P., Bueno, M. J., Zagorac, I., Mondejar, T., Sanchez, J., Mourón, S., Muñoz, J., Gómez-López, G., Jimenez-Renard, V., Mulero, F., Chandel, N. S., & Quintela-Fandino, M. (2016). Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics. Cell reports, 15(12), 2705-2718. https://doi.org/10.1016/j.celrep.2016.05.052