Endothelial p130cas confers resistance to anti-angiogenesis therapy

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. [Display omitted] •p130cas contributes to endothelial resistance to anti-VEGF antibody (AVA) therapy•Internalization of VEGFR2/p130cas occurs during AVA-induced endothelial cell death•TNKS1BP1 mediates cell death associated with nuclear p130cas/VEGFR2•Targeting vascular p130cas extends survival of AVA-resistant ovarian tumors The scaffolding protein p130cas is important during integrin-mediated angiogenesis under VEGF-A stimulation. Wen et al. discover that internalization of VEGFR2/p130cas fragments in endothelial cells, followed by TNKS1BP1-mediated cell death, is responsible for angiogenesis inhibition with AVA therapy. Targeting endothelial p130cas defers adaptive resistance to AVA therapy and reduces tumor growth.