Journal
MOLECULAR CANCER
Volume 21, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12943-022-01519-7
Keywords
METTL7B; TKIs resistance; Glutathione metabolism; m(6)A modification; Lung adenocarcinomas
Categories
Funding
- 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]
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This study demonstrates the crucial role of METTL7B in inducing resistance to EGFR-TKIs in lung adenocarcinoma. By regulating the mRNA modification of GPX4, HMOX1, and SOD1, METTL7B influences glutathione metabolism and drug sensitivity. These findings suggest that METTL7B inhibitors could serve as a potential treatment strategy for reversing EGFR-TKIs resistance in LUAD patients.
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.
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