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

Molecular Cancer (Feb 2022)

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

Affiliations

Huibin Song: 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
Dongcheng Liu: 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
Lingwei Wang: 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
Kaisheng Liu: 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
Chen Chen: 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
Le Wang: Department of Biomedical Engineering, Southern University of Science and Technology, Nanshan District
Yi Ren: 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
Bing Ju: 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
Fuhua Zhong: 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
Xingyu Jiang: Department of Biomedical Engineering, Southern University of Science and Technology, Nanshan District
Guangsuo Wang: Department of Thoracic Surgery, The First Affiliated Hospital of Southern, University of Sciences and Technology, Shenzhen People’s Hospital
Zhe-Sheng Chen: College of Pharmacy and Health Sciences, St. John’s University
Chang Zou: 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

DOI: https://doi.org/10.1186/s12943-022-01519-7
Journal volume & issue: Vol. 21, no. 1
pp. 1 – 20

Abstract

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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.

Published in Molecular Cancer

ISSN: 1476-4598 (Online)
Publisher: BMC
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://molecular-cancer.biomedcentral.com/

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