Enzymatic depletion ofl‐Met using an engineered human enzyme as a novel therapeutic strategy for melanoma
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ABSTRACT:
PROVIDER: PRJNA986092 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24982005_1.fastq.gz | Fastqsanger.gz | |||
| SRR24982005_2.fastq.gz | Fastqsanger.gz | |||
| SRR24982006_1.fastq.gz | Fastqsanger.gz | |||
| SRR24982006_2.fastq.gz | Fastqsanger.gz | |||
| SRR24982007_1.fastq.gz | Fastqsanger.gz |
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Project description:Many cancers, including melanoma, have a higher requirement forl‐methionine in comparison with noncancerous cells. In this study, we use a multiomics approach to show that administration of an engineered human methionine‐γ‐lyase (hMGL) significantly reduced the survival of both human and mouse melanoma cells in vitro.
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Project description:Targeting the MET oncoprotein is an effective strategy in precision cancer therapy, whereas its clinical efficacy varies dramatically across tumor types. To address this challenge, we explored an alternative approach to downregulate MET expression at transcriptional levels. We identified a cis-regulatory element in the MET proximal promoter region that folds into a stable parallel DNA G-quadruplex (MET-G4). We further determined the high-resolution NMR solution structure of MET-G4 and demonstrated that MET-G4 recruits the cellular LRPPRC protein to promote MET transcription, thereby uncovering a previously unrecognized epigenetic mechanism that drives MET overexpression. Moreover, we characterized the specific G4-binding domain of LRPPRC and elucidated its structural basis for recognition of the MET-G4. Through screening an in-house natural product library, we identified nitidine alkaloid (NIT) as a potent MET-G4 stabilizer. Strikingly, nitidine acts as a molecular glue, strengthening the LRPPRC-MET-G4 interaction and inducing the formation of a stable LRPPRC-NIT-MET-G4 ternary complex. This complex likely alters the structure and function of LRPPRC, ultimately leading to MET downregulation and potent anticancer effects. Notably, this is the first report of a molecular glue that stabilizes a G4-protein complex to silence an oncogene. Additionally, comprehensive in vitro and in vivo experiments demonstrated that nitidine significantly inhibits tumor progression mainly through an LRPPRC-MET-G4-dependent mechanism. Collectively, our study reveals a novel epigenetic regulatory mechanism involving LRPPRC-MET-G4-mediated MET upregulation and suggests a promising therapeutic strategy for MET-driven tumors with molecular glues that target the LRPPRC-MET-G4 interface
2026-05-19 | GSE330177 | GEO
Project description:This study investigates the mechanisms of resistance to MET-targeted therapy in MET-amplified lung cancer. Researchers established a lung cancer cell line resistant to MET tyrosine kinase inhibitors (MET-TKI) and found that Aurora kinase B (AURKB) inhibitors significantly inhibited the proliferation of these resistant cells. AURKB knockdown enhanced MET-TKI sensitivity, though the phosphorylation of Histone H3, an AURKB target, remained unchanged. Gene expression analysis revealed an enrichment of STAT3-activated genes, and AURKB influenced the phosphorylation of STAT3. The study also identified an elevated expression of the anti-apoptotic gene BCL2, and AURKB inhibition induced apoptosis by reducing the STAT3/BCL2 axis. The effects of AURKB inhibitors led to G2/M cell cycle arrest and apoptosis in resistant cells. AURKB overexpression was observed in post-treatment tumors from advanced MET-amplified lung cancer patients with MET-TKI resistance. This suggests that targeting AURKB may be a potential therapeutic strategy to overcome resistance to MET-TKIs in MET-amplified lung cancer.
2026-06-30 | GSE285996 | GEO
Project description:MET exon 14 skipping mutations (METΔex14) are oncogenic drivers in ~3-5% of lung cancer, which can be targeted with MET tyrosine kinase inhibitors (TKIs). The emergence of resistance limits long-term responses and is commonly mediated by secondary genomic alterations. We devised a preclinical strategy to study MET-TKI resistance using a novel dose escalation approach on METΔex14-dependent cancer cells to generate MET-TKI-refractory isogenic counterparts. Targeted sequencing of resistant clones identified acquired mutations in SPOP and MGA, both antagonists of MYC activity. Further investigation of SPOP and MGA interactomes confirmed MYC as the likeliest target shared between their regulatory networks. SPOP- and MGA-mutant clones exhibited high MYC levels and transcriptomic signatures of MYC activation. Ectopic expression of MYC rescued tumor growth in the presence of TKI, while MYC depletion mimicked the cytotoxic effect of TKI treatment, indicating that MYC activity is coupled to MET signaling and MYC is required to mediate drug resistance. Analysis of a clinical cohort of METΔex14-positive lung cancer revealed several cases where acquired MYC pathway alterations mediated resistance to MET-TKIs. These findings collectively converge on MYC as a key pathway in the progression of MET TKI-resistant cancers, and our in vitro data support the strategy of co-targeting MYC and MET to yield more prolonged responses in patients with METΔex14-positive lung cancer.
2026-05-21 | GSE298399 | GEO
Project description:Packaging genomic regions into silenced heterochromatin is critical to maintain organismal viability and tissue identity. Methylation of histone H3 on lysine 9 (H3K9me) marks heterochromatin. Here we show that in addition to catalyzing H3K9me, the C. elegans histone methyltransferase MET-2 (SETDB1-like) has a second non-catalytic function that can itself contribute to gene repression. We find that subnuclear concentrates, or foci, of MET-2 correlate with efficient HMT activity, yet foci composed of catalytic-deficient MET-2 are also able to mediate transcriptional silencing. Genetic ablation of met-2 or physiological disruption of MET-2 foci by heat stress results in loss of silencing coincident with an increase in histone acetylation. Restoration of catalytically deficient MET-2 foci mitigates H3K9 and H3K27 hyperacetylation, gene derepression, and infertility, demonstrating a structural role for foci of a conserved heterochromatic histone methyltransferase in gene silencing independent of its enzymatic activity.
2021-08-01 | GSE168924 | GEO
Project description:Packaging genomic regions into silenced heterochromatin is critical to maintain organismal viability and tissue identity. Methylation of histone H3 on lysine 9 (H3K9me) marks heterochromatin. Here we show that in addition to catalyzing H3K9me, the C. elegans histone methyltransferase MET-2 (SETDB1-like) has a second non-catalytic function that can itself contribute to gene repression. We find that subnuclear concentrates, or foci, of MET-2 correlate with efficient HMT activity, yet foci composed of catalytic-deficient MET-2 are also able to mediate transcriptional silencing. Genetic ablation of met-2 or physiological disruption of MET-2 foci by heat stress results in loss of silencing coincident with an increase in histone acetylation. Restoration of catalytically deficient MET-2 foci mitigates H3K9 and H3K27 hyperacetylation, gene derepression, and infertility, demonstrating a structural role for foci of a conserved heterochromatic histone methyltransferase in gene silencing independent of its enzymatic activity.
2021-08-01 | GSE168923 | GEO
Project description: Not available
| S-EPMC10900206 | biostudies-literature
Project description:To investigate the expression patterns driven by hyperactivated MET in MET-dependent cells, we employed LoVo colon adenocarcinoma cell line, harbouring a post-translational modification of MET that leads to its constitutive activation. We then silenced MET in LoVo cells using CRISPR/Cas9 knock-out (KO) protocol, and performed gene expression profiling analysis using data obtained from RNA-seq of cells with hyperactivated-MET versus MET-KO.
2023-10-14 | GSE212835 | GEO
Project description:Purpose: MET is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). To understand the mechanisms of resistance to MET-TKIs and establish therapeutic strategies, we developed an in vitro model using capmatinib-resistant cell lines (EBC-CR1, CR2, and CR3) derived from the MET-amplified NSCLC cell line EBC-1. Methods: We established capmatinib-resistant NSCLC cell lines from the MET-amplified NSCLC cell line EBC-1 and identified alternative signaling pathways using 3’mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative PCR and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the EBC-CR1, -CR2, and -CR3 resistant cell lines. Results: We found that epidermal growth factor (EGFR) mRNA expression and protein activation were increased in EBC-CR1–3 cells compared to EBC-1 cells. EBC-CR1 cells showed EGFR-dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells, which overexpressed the EGFR-MET heterodimer, responded dramatically to the combination of capmatinib and the phosphoinositide-3 kinase catalytic subunit α (PIK3CA) inhibitor afatinib. In addition, EBC-CR3 cells, which had activated EGFR along with amplified PIK3CA, were sensitive to the combination of afatinib and the PI3Kα inhibitor. Conclusions: Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be an effective therapeutic strategy in MET-TKI-resistant NSCLC patients.
2017-05-01 | GSE94405 | GEO