EGFR Blockade Reverses Cisplatin Resistance in Human Epithelial Ovarian Cancer Cells.

Abstract

Background:EOC is one of the most lethal gynecological malignancy worldwide. Although the majority of EOC patients achieve clinical remission after induction therapy, over 80% relapse and succumb to the chemoresistant disease. Previous investigations have demonstrated the association of EGFR with resistance to cytotoxic chemotherapies, hormone therapy, and radiotherapy in the cancers. These studies have highlighted the role of EGFR as an attractive therapeutic target in cisplatin-resistant EOC cells. Methods:The human ovarian cell lines (SKOV3 and OVCAR3) were cultured according to ATCC recommendations. The MTT assay was used to determine the chemosensitivity of the cell lines in exposure to cisplatin and erlotinib. The qRT-PCR was applied to analyze the mRNA expression of the desired genes. Results:Erlotinib in combination with cisplatin reduced the cell proliferation in the chemoresistant EOC cells in comparison to monotherapy of the drugs (p < 0.05). Moreover, erlotinib/cisplatin combination synergistically decreased the expression of anti-apoptotic and also increased pro-apoptotic genes expression (p < 0.05). Cisplatin alone could increase the expression of MDR genes. The data suggested that EGFR and cisplatin drive chemoresistance in the EOC cells through MEKK signal transduction as well as through EGFR/MEKK pathways in the cells, respectively. Conclusion: Our findings propose that EGFR is an attractive therapeutic target in chemoresistant EOC to be exploited in translational oncology, and erlotinib/cisplatin combination treatment is a potential anti-cancer approach to overcome chemoresistance and inhibit the proliferation of the EOC cells.