EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells

Hao Gong,Jun Chen,Chen Chen,Weiting Li,Chao Liu,Zihe Zhang,Minghui Liu,Hongyu Liu,Yongwen Li,Hongbing Zhang,Yin Yuan,Ruifeng Shi

doi:10.1186/s12885-020-07667-7

Abstract

BackgroundLung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells.MethodsThe RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting.ResultsEZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo.ConclusionsThese data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.

Highlights

Lung cancer is the leading cause of cancer-related deaths worldwide
The current common practices involve the administration of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) as first-line treatment to patients with EGFR-sensitive mutations because these drugs have been shown to considerably prolong progression-free survival while causing fewer adverse effects than chemotherapy [9].EGFR-TKIs have been approved as the second- or third-line treatment for EGFR wild-type (EGFR-wild type (WT)) Non-small cell lung cancer (NSCLC)
We demonstrated that Enhancer of zeste homolog 2 (EZH2) was upregulated in human NSCLC tissues and that this upregulation was correlated with poor prognosis in patients with lung adenocarcinoma (LUAD)

Summary

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. A profound understanding of the molecular mechanisms contributing to the development and progression of NSCLC is essential for developing specific diagnostic methods,as well as for designing individualized and effective physiological strategies. Targeted drugs such as epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) represent one of the vital advances in lung cancer treatment. The current common practices involve the administration of EGFR-TKIs as first-line treatment to patients with EGFR-sensitive mutations because these drugs have been shown to considerably prolong progression-free survival while causing fewer adverse effects than chemotherapy [9].EGFR-TKIs have been approved as the second- or third-line treatment for EGFR wild-type (EGFR-WT) NSCLC. The use of these targeted drugs beyond first-line treatment remains controversial, for the treatment of EGFR-WT NSCLC

Objectives

Methods

Results

Discussion

Conclusion