FOXM1 confers resistance to gefitinib in lung adenocarcinoma via a MET/AKT-dependent positive feedback loop.

Yu Wang,Ning Wen,Huiling Yang,Yuyu Yun,Yu Li,Erping Luo,Li Tian,Wenchao Liu,Li Wen,Mingling Wen,Weiwei Zhang,Lisheng Zhao,Xiaofei Zhu

doi:10.18632/oncotarget.11043

Abstract

Gefitinib resistance remains a major problem in the treatment of lung adenocarcinoma. However, the molecular mechanisms of gefitinib resistance are not fully understood. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in gefitinib resistance of lung adenocarcinoma cells. In vitro drug sensitivity assays demonstrated that FOXM1 inhibition sensitized PC9/GR and HCC827/GR cells to gefitinib, whereas FOXM1 overexpression enhanced PC9 and HCC827 cell resistance to gefitinib. Increased FOXM1 resulted in the upregulation of hepatocyte growth factor receptor (MET), which led to activation of the protein kinase B (AKT) pathway, whereas knockdown of FOXM1 did the opposite. FOXM1 bound directly to the MET promoter regions and regulated the promoter activities and the expression of MET at the transcriptional level. Moreover, MET/AKT pathway upregulated the expression of FOXM1 in lung adenocarcinoma cells. Inhibition of pAKT by LY294002 or inhibition of pMET by PHA-665752 significantly inhibited the expression of FOXM1 in lung adenocarcinoma cells. Importantly, we further demonstrated that the expression levels of FOXM1, pAKT and MET were significantly increased in lung adenocarcinoma tissues relative to normal lung tissues, and these three biomarkers were concomitantly overexpressed in lung adenocarcinoma tissues. Taken together, our results indicate that FOXM1 promotes acquired resistance to gefitinib of lung adenocarcinoma cells, and FOXM1 crosstalks with MET/AKT signaling to form a positive feedback loop to promote lung adenocarcinoma development.

Highlights

According to new statistics offered by the American Cancer Society, lung cancer is the first most common cause of cancer-related death and the most lethal cancer in the United States [1]
The function of Forkhead box protein M1 (FOXM1) was reported to be mediated by PI3K/AKT signaling pathway [21, 37,38,39]. These findings suggest that MET/AKT/ FOXM1 signaling pathway may play an important role in the resistance of lung adenocarcinoma cells to gefitinib
FOXM1 was a downstream target of AKT signalling, and there was a positive feedback regulation between FOXM1 and the MET/AKT signaling pathway in lung adenocarcinoma cells

Summary

Introduction

According to new statistics offered by the American Cancer Society, lung cancer is the first most common cause of cancer-related death and the most lethal cancer in the United States [1]. In 2015, it is estimated that new cases and deaths from lung cancer in the United States was 221,200 and 158,040, respectively [1]. Adenocarcinoma is the most common type of lung cancer accounting for 40% of all cases with its incidence increasing [2, 3]. Several mechanisms underlying acquired resistance to EGFR-TKIs have been identified, including secondary EGFR T790M mutation, MET amplification and HER2 amplification [9,10,11]. Elucidation of novel mechanisms underlying the acquired resistance to EGFR-TKIs is important for developing personalized therapeutics to treat patients with lung adenocarcinoma

Methods

Results

Conclusion