Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma

Molecular Cancer

Zhe-Sheng Chen¹  Xingyu Jiang²  Le Wang²  Fuhua Zhong³  Yi Ren³  Kaisheng Liu³  Bing Ju³  Chen Chen³  Dongcheng Liu⁴  Huibin Song⁵  Chang Zou⁶  Lingwei Wang⁷  Guangsuo Wang⁸ 

[1] College of Pharmacy and Health Sciences, St. John’s University, New York, USA;Department of Biomedical Engineering, Southern University of Science and Technology, Nanshan District, No. 1088 Xueyuan Rd, Shenzhen, Guangdong, China;Department of Clinical Medical Research Center, The First Affiliated Hospital of Southern, The 2nd Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, University of Science and Technology, 518020, Shenzhen, China;Department of Clinical Medical Research Center, The First Affiliated Hospital of Southern, The 2nd Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, University of Science and Technology, 518020, Shenzhen, China;Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, 510632, Guangzhou, China;Department of Clinical Medical Research Center, The First Affiliated Hospital of Southern, The 2nd Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, University of Science and Technology, 518020, Shenzhen, China;Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, 510632, Guangzhou, China;Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Southern, University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen Institute of Respiratory Diseases, 518020, Shenzhen, China;Department of Clinical Medical Research Center, The First Affiliated Hospital of Southern, The 2nd Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, University of Science and Technology, 518020, Shenzhen, China;Shenzhen Public Service Platform On Tumor Precision Medicine and Molecular Diagnosis, the Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, 518020, Shenzhen, China;School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China;Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Southern, University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen Institute of Respiratory Diseases, 518020, Shenzhen, China;Department of Thoracic Surgery, The First Affiliated Hospital of Southern, University of Sciences and Technology, Shenzhen People’s Hospital, Shenzhen, China;

关键词: METTL7B;    TKIs resistance;    Glutathione metabolism;    mA modification;    Lung adenocarcinomas;   

DOI  :  10.1186/s12943-022-01519-7

来源: Springer

【 摘 要 】

BackgroundIdentification of potential novel targets for reversing resistance to Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) holds great promise for the treatment of relapsed lung adenocarcinoma (LUAD). In the present study, we aim to investigate the role of methyltransferase-like 7B (METTL7B) in inducing EGFR-TKIs resistance in LUAD and whether it could be a therapeutic target for reversing the resistance.MethodsMETTL7B-overexpressed LUAD cell lines, gefitinib and osimertinib-resistant Cell-Derived tumor Xenograft (CDX) and Patient-Derived tumor Xenograft (PDX) mouse models were employed to evaluate the role of METTL7B in TKIs resistance. Ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was used to identify the metabolites regulated by METTL7B. Methylated RNA immunoprecipitation (MeRIP)-qPCR analysis was performed to measure the N6-methyladenosine (m6A) status of mRNA of METTL7B targeted genes. Gold nanocluster-assisted delivery of siRNA targeting METTL7B (GNC-siMETTL7B) was applied to evaluate the effect of METTL7B in TKIs resistance.ResultsIncreased expression of METTL7B was found in TKIs-resistant LUAD cells and overexpression of METTL7B in LUAD cells induced TKIs resistance both in vitro and in vivo. Activated ROS-metabolism was identified in METTL7B-overexpressed LUAD cells, accompanied with upregulated protein level of GPX4, HMOX1 and SOD1 and their enzymatic activities. Globally elevated m6A levels were found in METTL7B-overexpressed LUAD cells, which was reduced by knock-down of METTL7B. METTL7B induced m6A modification of GPX4, HMOX1 and SOD1 mRNA. Knock-down of METTL7B by siRNA re-sensitized LUAD cells to gefitinib and osimertinib both in vitro and in vivo.ConclusionsThis study uncovered a new critical link in METTL7B, glutathione metabolism and drug resistance. Our findings demonstrated that METTL7B inhibitors could be used for reversing TKIs resistance in LUAD patients.

【 授权许可】

CC BY