Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. 
Despite initial therapeutic response, the majority of advanced-stage patients 
relapse and succumb to chemoresistant disease. Overcoming drug resistance is the 
key to successful treatment of EOC. Members of vascular endothelial growth 
factor (VEGF) family are overexpressed in EOC and play key roles in its 
malignant progression though their contribution in development of the 
chemoresistant disease remains elusive. Here we show that expression of the VEGF 
family is higher in therapy-resistant EOC cells compared to sensitive ones. 
Overexpression of VEGFR2 correlated with resistance to cisplatin and combination 
with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. 
Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the 
chemoresistant EOC cells through induction of G2/M cell cycle arrest and 
apoptotic cell death. Tivozanib decreased invasive potential of these cells, 
concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and 
diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) 
and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically 
enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. 
These findings suggest that the VEGF pathway has potential as a therapeutic 
target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield 
stronger anti-tumour efficacy and circumvent resistance to EGFR-directed 
therapies.