Jaiprasart Pharavee, Dogra Samrita, Neelakantan Deepika, Devapatla Bharat, Woo Sukyung
Department of Pharmaceutical Sciences, College of Pharmacy, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Gynecologic Cancers Research Program, Peggy and Charles Stephenson Cancer Center, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oncotarget. 2020 Jan 7;11(1):99-114. doi: 10.18632/oncotarget.27307.
VEGF-mediated tumor angiogenesis is a validated clinical target in many cancers, but modest efficacy and rapid development of resistance are major challenges of VEGF-targeted therapies. To establish a molecular signature of this resistance in ovarian cancer, we developed preclinical tumor models of adaptive resistance to chronic anti-VEGF treatment. We performed RNA-seq analysis and reverse-phase protein array to compare changes in gene and protein expressions in stroma and cancer cells from resistant and responsive tumors. We identified a unique set of stromal-specific genes that were strongly correlated with resistance phenotypes against two different anti-VEGF treatments, and selected the apelin/APJ signaling pathway for further validation. Using various functional assays, we showed that activation of apelin/APJ signaling reduces the efficacy of a VEGF inhibitor in endothelial cells. In patients with ovarian cancer treated with bevacizumab, increased expression of apelin was associated with significantly decreased disease-free survival. These findings link signature gene expressions with anti-VEGF response, and may thus provide novel targetable mechanisms of clinical resistance to anti-VEGF therapies.
血管内皮生长因子（VEGF）介导的肿瘤血管生成是许多癌症中已得到验证的临床靶点，但疗效有限以及耐药性的快速产生是VEGF靶向治疗的主要挑战。为了建立卵巢癌中这种耐药性的分子特征，我们开发了对慢性抗VEGF治疗产生适应性耐药的临床前肿瘤模型。我们进行了RNA测序分析和反相蛋白质阵列分析，以比较耐药和敏感肿瘤的基质细胞和癌细胞中基因和蛋白质表达的变化。我们鉴定出一组独特的基质特异性基因，它们与针对两种不同抗VEGF治疗的耐药表型密切相关，并选择阿片肽/APJ信号通路进行进一步验证。通过各种功能试验，我们发现激活阿片肽/APJ信号会降低VEGF抑制剂在内皮细胞中的疗效。在接受贝伐单抗治疗的卵巢癌患者中，阿片肽表达增加与无病生存期显著缩短相关。这些发现将特征性基因表达与抗VEGF反应联系起来，因此可能为临床抗VEGF治疗耐药性提供新的可靶向机制。
