Objective: Aberrant epidermal growth factor receptor (EGFR) is involved in a variety of cancers and its inhibitors have been studied for over a decade. We aim to investigate the effects of dacomitinib, a second generation pan-EGFR inhibitor, on ovarian cancer cells.
Methods: By immunohistochemistry, we studied the clinical significance of EGFR expression in epithelial ovarian cancer (EOC). The correlations between EGFR expression and the clinicopathological variables of patients with EOC were assessed using Pearson's X2 test. Kaplan-Meier analysis was used to compare the postoperative survival between groups of patients with EOC with varying levels of EGFR expression. MTT, caspase assay, cell apoptosis analysis, autophagy analysis, cell cycle analysis, and western blotting were used to investigate various effects of dacomitinib in cell proliferation, apoptosis, and associated molecular pathways.
Results: High expression of EGFR was found to be associated with poor prognosis of patients with EOC. EGFR, P-AKT, and P-ERK were inhibited after treatment of dacomitinib in both SKOV3 and OV4 cells. Activations of caspase activities, apoptosis, and autophagy were also observed and confirmed by western blot: caspase 9, LC3, and Bax levels were elevated, while Bcl-2 and Bcl-xl were down-regulated. The percentage of cancer cells in the S and G2 phases of the cell cycle significantly decreased after treatment. Cdk1 and Cdk2 protein levels declined after dacomitinib treatment; epithelial-mesenchymal transition (EMT) was inhibited, which was confirmed by observing E-cadherin, N-cadherin, and slug inhibition. Additionally, dacomitinib significantly increased chemotherapy sensitivity in chemotherapeutic resistant ovarian cell lines, C13 and 2780CP.
Conclusion: Our data showed that increased expression of EGFR is associated with poor prognosis of patients with EOC and dacomitinib may act as a novel, useful chemotherapy drug. Further studies are warranted.