Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy.

Pharavee Jaiprasart,Sukyung Woo,Bharat Devapatla,Samrita Dogra,Deepika Neelakantan

doi:10.18632/oncotarget.27307

Abstract

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 in vitro 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.

Highlights

Ovarian cancer is the principal cause of gynecological-cancer-related deaths in women in the United States [1]
To identify the molecular changes in ovarian tumors that progress despite anti-vascular endothelial growth factor (VEGF) therapy, we developed a preclinical model for adaptive resistance, wherein the tumor-bearing mice received anti-VEGF treatment for two months
We used two different inhibitors against the VEGF pathway: bevacizumab, the monoclonal antibody that blocks the ligand VEGF secreted by the tumor cells, and sorafenib, a small-molecule tyrosine kinase inhibitor (TKI) that targets VEGF receptor (VEGFR) expressed by both endothelial cells and cancer cells

Summary

Introduction

Ovarian cancer is the principal cause of gynecological-cancer-related deaths in women in the United States [1]. Several studies have shown that a high level of vascular endothelial growth factor (VEGF), a key regulator of tumor angiogenesis, is associated with poor prognosis in patients with ovarian cancer [5, 6]. Several phase III clinical studies have shown that VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) significantly increase progression-free survival (PFS) when used as maintenance therapy [9]. Together, these data suggest that anti-angiogenic strategies are a valid and important treatment option for ovarian cancer. There is an urgent need to identify biological markers implicated in the resistance to anti-VEGF drugs, which would aid in the early detection of resistance development, and to monitor responders. The identified markers would provide www.oncotarget.com important alternative therapeutic strategies to improve the clinical benefit of anti-angiogenic drugs

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Results

Conclusion