Cell Reports (Jan 2022)

Endothelial p130cas confers resistance to anti-angiogenesis therapy

  • Yunfei Wen,
  • Anca Chelariu-Raicu,
  • Sujanitha Umamaheswaran,
  • Alpa M. Nick,
  • Elaine Stur,
  • Pahul Hanjra,
  • Dahai Jiang,
  • Nicholas B. Jennings,
  • Xiuhui Chen,
  • Sara Corvigno,
  • Deanna Glassman,
  • Gabriel Lopez-Berestein,
  • Jinsong Liu,
  • Mien-Chie Hung,
  • Anil K. Sood

Journal volume & issue
Vol. 38, no. 4
p. 110301

Abstract

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Summary: 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.

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