Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer
10.1016/j.jpha.2023.04.009
- Author:
Han XIAO
1
;
Rong ZHAO
;
Wangyang MENG
;
Yongde LIAO
Author Information
1. Department of Thoracic Surgery,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430022,China
- Keywords:
STM2457;
METTL3;
Translatomics;
Non-small cell lung cancer;
PD-L1
- From:
Journal of Pharmaceutical Analysis
2023;13(6):625-639
- CountryChina
- Language:Chinese
-
Abstract:
In non-small cell lung cancer(NSCLC),the heterogeneity promotes drug resistance,and the restricted expression of programmed death-ligand 1(PD-L1)limits the immunotherapy benefits.Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferase-like 3(METTL3),the novel small-molecule inhibitor STM2457 is assumed to be useful for the treat-ment of NSCLC.We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression.Next,we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression.Importantly,we described the genome-wide characteristics of multiple omics data ac-quired from RNA sequencing,ribosome profiling,and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout.We also constructed a model for the regulation of the translation of METTL3 and PD-L1.Finally,we found PD-Ll upregulation by STM2457 in vivo and in vitro.In conclusion,STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome.Furthermore,it can improve the immunotherapy outcomes based on PD-L1 upregulation in NSCLC.
