| First Author | Wen Y | Year | 2022 |
| Journal | Cell Rep | Volume | 38 |
| Issue | 4 | Pages | 110301 |
| PubMed ID | 35081345 | Mgi Jnum | J:327101 |
| Mgi Id | MGI:6879584 | Doi | 10.1016/j.celrep.2022.110301 |
| Citation | Wen Y, et al. (2022) Endothelial p130cas confers resistance to anti-angiogenesis therapy. Cell Rep 38(4):110301 |
| abstractText | 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 p130cas(flox/flox)Tie2(Cre) 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. |
