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
Affiliations
Yunfei Wen
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA; Corresponding author
Anca Chelariu-Raicu
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Sujanitha Umamaheswaran
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Alpa M. Nick
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Elaine Stur
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Pahul Hanjra
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Dahai Jiang
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Nicholas B. Jennings
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Xiuhui Chen
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Sara Corvigno
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Deanna Glassman
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA
Gabriel Lopez-Berestein
Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jinsong Liu
Department of Pathology/Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Mien-Chie Hung
Graduate Institute of Biomedical Sciences, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
Anil K. Sood
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Boulevard, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Corresponding author
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.
