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

Song, Huibin1,2,3; Liu, Dongcheng1,2; Wang, Lingwei3; Liu, Kaisheng1; Chen, Chen1; Wang, Le4; Ren, Yi1; Ju, Bing1; Zhong, Fuhua1; Jiang, Xingyu4; Wang, Guangsuo5; Chen, Zhe-Sheng6; Zou, Chang1,7,8

2022-02-10

10.1186/s12943-022-01519-7

MOLECULAR CANCER   影响因子和分区

1476-4598

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 N-6-methyladenosine (m(6)A) 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 m(6)A levels were found in METTL7B-overexpressed LUAD cells, which was reduced by knock-down of METTL7B. METTL7B induced m(6)A 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.

METTL7B TKIs resistance Glutathione metabolism m(6)A modification Lung adenocarcinomas

SCI

英语

其他

National Natural Science Foundation of China[32100609,32000427] ; Guangdong Basic and Applied Basic Research Foundation[2020B1515120032] ; Science and Technology Foundation of Shenzhen[JCYJ20210324115800001] ; Shenzhen Economic and Information Committee "Innovation Chain and Industry Chain" integration special support plan project[20180225112449943] ; Shenzhen Key Medical Discipline Construction Fund["SZXK053","SZXK018"] ; Shenzhen Healthcare Research Project[SZLY2017024] ; Shenzhen Science and Technology Program[JCYJ20210324113008020] ; Guangdong Provincial Natural Science Foundation[2018A030313743] ; Guangdong Innovative and the Entrepreneurial Research Team Program[2019ZT08Y191]

Biochemistry & Molecular Biology ; Oncology

Biochemistry & Molecular Biology ; Oncology

WOS:000753885600001

BMC

2-s2.0-85124445874

Web of Science

1.Jinan Univ, Clin Med Coll 2, Affiliated Hosp Southern 1, Dept Clin Med Res Ctr,Shenzhen Peoples Hosp,Univ, Shenzhen 518020, Peoples R China
2.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou 510632, Peoples R China
3.Jinan Univ, Univ Sci & Technol, Affiliated Hosp Southern 1,Shenzhen Inst Resp Dis, Shenzhen Peoples Hosp,Clin Med Coll 2,Dept Resp &, Shenzhen 518020, Peoples R China
4.Southern Univ Sci & Technol, Dept Biomed Engn, 1088 Xueyuan Rd, Shenzhen, Guangdong, Peoples R China
5.Univ Sci & Technol, Affiliated Hosp Southern 1, Shenzhen Peoples Hosp, Dept Thorac Surg, Shenzhen, Peoples R China
6.St Johns Univ, Coll Pharm & Hlth Sci, New York, NY 11439 USA
7.Jinan Univ, Shenzhen Peoples Hosp, Shenzhen Publ Serv Platform Tumor Precis Med & Mo, Clin Med Coll 2, Shenzhen 518020, Peoples R China
8.Chinese Univ Hong Kong, Sch Life & Hlth Sci, Shenzhen, Peoples R China

Song, Huibin,Liu, Dongcheng,Wang, Lingwei,et al. Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma[J]. MOLECULAR CANCER,2022,21(1).

Song, Huibin.,Liu, Dongcheng.,Wang, Lingwei.,Liu, Kaisheng.,Chen, Chen.,...&Zou, Chang.(2022).Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma.MOLECULAR CANCER,21(1).

Song, Huibin,et al."Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma".MOLECULAR CANCER 21.1(2022).