Dacomitinib, a new pan-EGFR inhibitor, is effective in killing ovarian cancer cells
Lei Xu1, Huini Wu2,3, Chao Jiang4,3
1Maternal and Child Health Hospital of Zibo City, Shandong 255022, China.
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.
Insights
Dacomitinib, an epidermal growth factor receptor (EGFR) inhibitor, shows promise in treating ovarian cancer. It inhibits tumor growth, induces apoptosis, and enhances chemotherapy sensitivity in resistant cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aberrant epidermal growth factor receptor (EGFR) signaling drives various cancers.
- EGFR inhibitors are a key therapeutic strategy in oncology.
- Ovarian cancer remains a significant health challenge with unmet therapeutic needs.
Purpose of the Study:
- To investigate the effects of dacomitinib, a second-generation pan-EGFR inhibitor, on ovarian cancer cells.
- To assess the clinical significance of EGFR expression in epithelial ovarian cancer (EOC).
- To explore dacomitinib's impact on cell proliferation, apoptosis, autophagy, cell cycle, and chemotherapy resistance.
Main Methods:
- Immunohistochemistry to evaluate EGFR expression in EOC.
- Statistical analysis (Pearson's X2, Kaplan-Meier) for clinical correlations and survival.
- In vitro assays (MTT, caspase, apoptosis, autophagy, cell cycle, western blotting) to determine dacomitinib's cellular effects.
- Assessment of dacomitinib's impact on chemotherapy-resistant ovarian cancer cell lines.
Main Results:
- High EGFR expression correlated with poor prognosis in EOC patients.
- Dacomitinib inhibited EGFR, P-AKT, and P-ERK signaling pathways.
- Dacomitinib induced apoptosis and autophagy, altered cell cycle progression, and inhibited epithelial-mesenchymal transition (EMT).
- Dacomitinib resensitized chemotherapy-resistant ovarian cancer cells to treatment.
Conclusions:
- Increased EGFR expression is linked to poor EOC prognosis.
- Dacomitinib demonstrates potential as a novel therapeutic agent for ovarian cancer.
- Further research is warranted to explore dacomitinib's clinical utility in ovarian cancer treatment.
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