Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal

Cell Metab. 2014 Aug 5;20(2):280-94. doi: 10.1016/j.cmet.2014.05.022. Epub 2014 Jul 10.


The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Cell Line, Tumor
  • Disease Progression
  • Fatty Acid Synthases / antagonists & inhibitors
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Indoles / therapeutic use
  • Lipids / biosynthesis*
  • Metabolomics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Metastasis
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Niacinamide / analogs & derivatives
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / therapeutic use
  • Proteomics
  • Pyrroles / therapeutic use
  • RNA Interference
  • Sorafenib
  • Sunitinib
  • Transplantation, Heterologous


  • Angiogenesis Inhibitors
  • Homeodomain Proteins
  • Indoles
  • Lipids
  • Phenylurea Compounds
  • Pyrroles
  • RAG-1 protein
  • Niacinamide
  • Sorafenib
  • Fatty Acid Synthases
  • Sunitinib

Associated data

  • GEO/GSE50795