Endothelial p130cas confers resistance to anti-angiogenesis therapy

Cell Reports

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