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

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.

Identification of Hub Genes and Key Pathways Associated with Anti-VEGF Resistant Glioblastoma Using Gene Expression Data Analysis

“…For instance, TSGA10 (testis specific Gene Antigen 10), which acts as a tumor suppressor in many types of human cancers [ 60 ] and inhibits VEGF -induced angiogenesis [ 61 ] was not differentially expressed in anti- VEGF resistant condition. Further, recent RNA seq analysis of anti- VEGF resistant ovarian cancer model showed upregulation of apelin/ APJ receptor signaling pathway [ 62 ]. However, this receptor-ligand pair gene expression was not altered in anti- VEGF resistant glioma described in the present study, probably suggesting that mechanisms underlying anti VEGF resistance are different in different tumors.…”

Favorable Prognostic Impact of Cathepsin H (CTSH) High Expression in Thyroid Carcinoma

“…A recent study showed that apelin inhibition could prevent resistance and metastasis associated with anti-angiogenic therapy. 23 , 24 Apelin was associated with the promotion of hepatocellular carcinoma through activating PI3K/Akt pathway and was a druggable target. 25 In addition, apelin can induce the lymphangiogenesis and, accordingly, play an important role in lymphatic tumor progression.…”

Roles of apelin/APJ system in cancer: Biomarker, predictor, and emerging therapeutic target

“…Hypoxia is the main driving force to initiate angiogenesis and promote tumor growth and metastasis. If the angiogenesis in the tumor is inhibited, the tumor can be effectively treated (Aktan & Ozmen, 2019; Haas et al, 2021; Jaiprasart et al, 2020; Kälin et al, 2007). The current existing antiangiogenesis therapy can cause various side effects, such as local hypoxia and tumor metastasis.…”

“…Apelin/APJ system can significantly reduce the therapeutic effect of VEGF inhibitors in patients with ovarian cancer. The efficacy of bevacizumab in patients with ovarian cancer can also be oppressed by apelin, resulting in a significant decrease in the disease‐free survival rate of patients and affecting their prognosis (Frontiers Editorial Office, 2021; Jaiprasart et al, 2020). In the lymph node tissues of patients with Stage III and IV ovarian cancer, the relevant immune response of apelin and APJ was detected, indicating that the apelin/APJ system plays a crucial role in the metastasis and prognosis of serous ovarian cancer (Köbel et al, 2008; Unal et al, 2020).…”