Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy
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Pharavee Jaiprasart1,*, Samrita Dogra1,*, Deepika Neelakantan1,*, Bharat Devapatla1 and Sukyung Woo1,2
1 Department of Pharmaceutical Sciences, College of Pharmacy, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
2 Gynecologic Cancers Research Program, Peggy and Charles Stephenson Cancer Center, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
* These authors contributed equally to this work
|Sukyung Woo,||email:||[email protected]|
Keywords: anti-VEGF resistance; angiogenesis; bevacizumab; next-generation sequencing (NGS); apelin
Received: May 21, 2019 Accepted: October 04, 2019 Published: January 07, 2020
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.
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