Cell Reports | |
Endothelial p130cas confers resistance to anti-angiogenesis therapy | |
Xiuhui Chen1  Anca Chelariu-Raicu2  Anil K. Sood3  Mien-Chie Hung4  Pahul Hanjra5  Gabriel Lopez-Berestein5  Yunfei Wen5  Elaine Stur5  Sara Corvigno5  Alpa M. Nick5  Sujanitha Umamaheswaran5  Nicholas B. Jennings5  Dahai Jiang5  Deanna Glassman5  Jinsong Liu5  | |
[1] Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Corresponding author;Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA; | |
关键词: p130cas; VEGFR2; autophagy; TNKS1BP1; adaptive resistance; anti-angiogenic therapy; | |
DOI : | |
来源: DOAJ |
【 摘 要 】
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.
【 授权许可】
Unknown