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

Huibin Song; Dongcheng Liu; Lingwei Wang; Kaisheng Liu; Chen Chen; Le Wang; Yi Ren; Bing Ju; Fuhua Zhong; Xingyu Jiang; Guangsuo Wang; Zhe-Sheng Chen; Chang Zou

doi:10.1186/s12943-022-01519-7

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

Mol Cancer. 2022 Feb 10;21(1):43. doi: 10.1186/s12943-022-01519-7.

Authors

Huibin Song^#^{1

2

3}, Dongcheng Liu^#^{1

2}, Lingwei Wang^#³, Kaisheng Liu^#¹, Chen Chen^#¹, Le Wang⁴, Yi Ren¹, Bing Ju¹, Fuhua Zhong¹, Xingyu Jiang⁴, Guangsuo Wang⁵, Zhe-Sheng Chen⁶, Chang Zou^{7

8

9}

Affiliations

¹ 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, Shenzhen, 518020, China.
² Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China.
³ 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, Shenzhen, 518020, China.
⁴ Department of Biomedical Engineering, Southern University of Science and Technology, Nanshan District, No. 1088 Xueyuan Rd, Shenzhen, Guangdong, China.
⁵ Department of Thoracic Surgery, The First Affiliated Hospital of Southern, University of Sciences and Technology, Shenzhen People's Hospital, Shenzhen, China. wgswy01@163.com.
⁶ College of Pharmacy and Health Sciences, St. John's University, New York, USA. chenz@stjohns.edu.
⁷ 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, Shenzhen, 518020, China. zou.chang@szhospital.com.
⁸ Shenzhen Public Service Platform On Tumor Precision Medicine and Molecular Diagnosis, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, 518020, China. zou.chang@szhospital.com.
⁹ School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China. zou.chang@szhospital.com.

^# Contributed equally.

Abstract

Background: Identification 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.

Methods: METTL7B-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.

Results: Increased 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.

Conclusions: This 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.

Keywords: Glutathione metabolism; Lung adenocarcinomas; METTL7B; TKIs resistance; m6A modification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Adenocarcinoma of Lung* / genetics
Adenocarcinoma of Lung* / pathology
Animals
Carrier Proteins*
Cell Line, Tumor
Chromatography, Liquid
Drug Resistance, Neoplasm
ErbB Receptors* / antagonists & inhibitors
ErbB Receptors* / metabolism
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / enzymology
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Methyltransferases / genetics
Methyltransferases / metabolism
Mice
Mutation
Protein Kinase Inhibitors* / pharmacology
Protein Kinase Inhibitors* / therapeutic use
Tandem Mass Spectrometry
Xenograft Model Antitumor Assays

Substances

Carrier Proteins
METTL7B protein, human
Protein Kinase Inhibitors
Methyltransferases
EGFR protein, human
ErbB Receptors