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

Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy.
Oncotarget. 2020 Jan 07;11(1):99-114
Authors: Jaiprasart P, Dogra S, Neelakantan D, Devapatla B, Woo S
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.
PMID: 320...

Source: Oncotarget - February 1, 2020 Category: Cancer & Oncology Tags: Oncotarget Source Type: research