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

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

doi:10.1186/s12943-022-01519-7

Cited by 40 publications

(33 citation statements)

References 73 publications

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“…Recently, Song et al. reported that METTL7B in lung adenocarcinoma reversed resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors by changing m6A modification ( 54 ). As a new molecule in glioma, we demonstrated that METTL7B participates in the cellular immune response by affecting the mRNA stability of PD-L1 and showed the critical role of m6A in this process.…”

Section: Discussionmentioning

confidence: 99%

A Whole Exon Screening-Based Score Model Predicts Prognosis and Immune Checkpoint Inhibitor Therapy Effects in Low-Grade Glioma

Luo

Wang

Shan³

et al. 2022

Front. Immunol.

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ObjectiveThis study aims to identify prognostic factors for low-grade glioma (LGG) via different machine learning methods in the whole genome and to predict patient prognoses based on these factors. We verified the results through in vitro experiments to further screen new potential therapeutic targets.MethodA total of 940 glioma patients from The Cancer Genome Atlas (TCGA) and The Chinese Glioma Genome Atlas (CGGA) were included in this study. Two different feature extraction algorithms – LASSO and Random Forest (RF) – were used to jointly screen genes significantly related to the prognosis of patients. The risk signature was constructed based on these screening genes, and the K-M curve and ROC curve evaluated it. Furthermore, we discussed the differences between the high- and low-risk groups distinguished by the signature in detail, including differential gene expression (DEG), single-nucleotide polymorphism (SNP), copy number variation (CNV), immune infiltration, and immune checkpoint. Finally, we identified the function of a novel molecule, METTL7B, which was highly correlated with PD-L1 expression on tumor cell, as verified by in vitro experiments.ResultsWe constructed an accurate prediction model based on seven genes (AUC at 1, 3, 5 years= 0.91, 0.85, 0.74). Further analysis showed that extracellular matrix remodeling and cytokine and chemokine release were activated in the high-risk group. The proportion of multiple immune cell infiltration was upregulated, especially macrophages, accompanied by the high expression of most immune checkpoints. According to the in vitro experiment, we preliminarily speculate that METTL7B affects the stability of PD-L1 mRNA by participating in the modification of m6A.ConclusionThe seven gene signatures we constructed can predict the prognosis of patients and identify the potential benefits of immune checkpoint inhibitors (ICI) therapy for LGG. More importantly, METTL7B, one of the risk genes, is a crucial molecule that regulates PD-L1 and could be used as a new potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

A Whole Exon Screening-Based Score Model Predicts Prognosis and Immune Checkpoint Inhibitor Therapy Effects in Low-Grade Glioma

Luo

Wang

Shan³

et al. 2022

Front. Immunol.

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“… 423 Similarly, METTL7B can increase the expression of GPX4, HMOX1, and SOD1 by m6A modification, leading to ferroptosis resistance and TKI resistance in LUAD (see Ferroptosis). 424 Moreover, METTL-KIAA1429 can enhance homeobox A1 (HOXA1) mRNA stability and lead to gefitinib resistance in NSCLC through HOXA1 expression, 425 but HOXA1 is considered an oncogene whose function is currently unknown. The m6A modification mediated by YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) can increase circRNA-ASK1 degradation, thereby attenuating the inhibitory effect of the circRNA-ASK1-encoded product ASK1-272a.a on AKT pathway and increasing LUAD resistance to gefitinib.…”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Yang

Wang

et al. 2022

Sig Transduct Target Ther

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Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.

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“…Aberrant regulation of m6A modification affects lung cancer prognosis and afatinib resistance ( 86 ). In LUAD, METTL7B is a potential therapeutic target for reversing gefitinib- and osimertinib-resistance by promoting three key reactive oxygen species scavengers (ROS) ( 87 , 88 ).The dysregulation of the FTO-m6A axis in leukemia cells is required for EGFR-TKI (tyrosine kinase inhibitors) resistance, which can be prevented or eradicated by specifically targeting FTO ( 89 ). In chronic myelogenous leukemia (CML), METTL3, and METTL14 are upregulated and affect sensitivity to TKI imatinib ( 90 ).…”

Section: Aberrant Regulation Of M6a Modification In Drug Resistancementioning

confidence: 99%

The emerging therapeutic target of dynamic and reversible N6-methyladenosine modification during cancer development

Liu

Chen²,

Tang³

et al. 2022

Front. Oncol.

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As a reversible and dynamic epigenetic modification, N6-methyladenosine (m6A) modification is ubiquitous in eukaryotic cells. m6A methylation is prevalent in almost all RNA metabolism processes that affect the fate of cells, including cancer development. As indicated by the available evidence, targeting m6A regulators may play a crucial role in tumor therapy and multidrug resistance. Currently, many questions remain uncovered. Here, we review recent studies on m6A modification in various aspects of tumor progression, tumor immunity, multidrug resistance, and therapeutic targets to provide new insight into the m6A methylation process.

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

Cited by 40 publications

References 73 publications

A Whole Exon Screening-Based Score Model Predicts Prognosis and Immune Checkpoint Inhibitor Therapy Effects in Low-Grade Glioma

A Whole Exon Screening-Based Score Model Predicts Prognosis and Immune Checkpoint Inhibitor Therapy Effects in Low-Grade Glioma

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

The emerging therapeutic target of dynamic and reversible N6-methyladenosine modification during cancer development

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