Endothelial p130cas confers resistance to anti-angiogenesis therapy

Cell Rep. 2022 Jan 25;38(4):110301. doi: 10.1016/j.celrep.2022.110301.

Abstract

Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy.

Keywords: TNKS1BP1; VEGFR2; adaptive resistance; angiogenesis; anti-angiogenic therapy; autophagy; p130cas.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiogenesis Inhibitors / pharmacokinetics
  • Animals
  • Bevacizumab / pharmacology
  • Crk-Associated Substrate Protein / metabolism*
  • Drug Resistance, Neoplasm / physiology*
  • Endothelial Cells / metabolism*
  • Female
  • Humans
  • Mice
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Crk-Associated Substrate Protein
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • Vascular Endothelial Growth Factor Receptor-2