Ezh2 Inhibitors Reverse Resistance to Gefitinib in Primary Egfr Wild-type Lung Cancer Cells
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Hao Gong, Yongwen Li, Yin Yuan, Weiting Li, Hongbing Zhang, Zihe Zhang, Ruifeng Shi, Minghui Liu, Chao Liu, Hongyu Liu, Jun Chen
2020
unpublished
Background: Lung cancer is the leading cause of cancer-related death worldwide. Non–small-cell lung cancer (NSCLC) is the most common type of lung cancer. Traditional anticancer therapies involving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) have been proven beneficial in the treatment of patients with EGFR mutations. However, patients with EGFR wild-type NSCLC usually fail to respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2), a key molecule of the PRC2
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... complex, plays an important role in epigenetic regulation and is overexpressed in various tumors. EZH2 inhibitors sensitize various types of tumor cells to antitumor drugs. Therefore, this study aimed to investigate whether the EZH2 inhibitors GSK343 and DZNep, whencombined with gefitinib, can reverse EGFR-TKI resistance in EGFR wild-type NSCLC. Methods:EZH2 expression was evaluated using the RNA sequencing dataset of NSCLC patients (502 lung squamous cell carcinoma cases including 49 paracancerous lung tissues and 513 lung adenocarcinoma cases including 59 paracancerous lung tissues) from The Cancer Genome Atlas (TCGA). We simultaneously also verified EZH2 expressionin 40 NSCLC samples and their corresponding paracancerous lung tissues from our institution via quantitative PCR. The lung adenocarcinoma cell lines A549 and H1299 were treated with EZH2-specific small interfering RNA or EZH2 inhibitors and subjected to analyses of cell viability and apoptosis as well as of EGFR pathway protein expressions by western blotting. Results: EZH2 was upregulated in human NSCLC tissues and was correlated with poor prognosis in patients with lung adenocarcinoma based on data from both TCGA and our institution. Both EZH2 inhibitors sensitized A549 and H1299 cells to gefitinib and suppressed cell viability and proliferation in vitroby downregulating the phosphorylation of EGFR and AKT and inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted stronger inhibitory effects on tumor activity, cell proliferation, and cell migration than single drug administration in vitro and in vivo.Conclusion: Co-administration of EZH2 inhibitors with EGFR-TKIs may be feasible for the treatment of EGFR wild-type NSCLC in patients who refuse traditional chemotherapy.
doi:10.21203/rs.3.rs-33892/v1
fatcat:u2vqkiq6rfeftbtnk7qd4y5e74