Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1143082 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30101444_subreads.fastq.gz | Fastqsanger.gz | |||
| SRR30101445_subreads.fastq.gz | Fastqsanger.gz | |||
| SRR30101446_subreads.fastq.gz | Fastqsanger.gz | |||
| SRR30101447_subreads.fastq.gz | Fastqsanger.gz | |||
| SRR30101448_subreads.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
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Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAFand MEK1/2 in PTEN null, BRAFV600E cells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with inhibitors for mutant BRAF/MEK1/2 identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600E cells. The findings indicate PTEN null BRAFV600E melanoma becomes dependent on ERBB/HER signaling when treated with clinically approved BRAF and MEK inhibitors. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.
2024-04-23 | PXD033866 | Pride
Project description:Phosphates and tensin homolog (PTEN) is a critical tumor suppressor, and even partial reduction of PTEN levels increases cancer susceptibility. PTEN loss frequently occurs in non-small cell lung carcinoma (NSCLC) and is associated with poor diagnosis. However, there are no effective interventions available to prevent or restore PTEN loss. CREB binding protein (CREBBP or CBP) is a well-known acetyltransferase. PTEN loss in lung cancer carrying CBP loss-of-function (LOF) mutations has not been addressed. Here, we showed that the decreased acetylation of histone deacetylase 3 (HDAC3) due to CBP LOF mutations contributes to PTEN loss in lung cancer. HDAC3 is a member of the class I histone deacetylase family. We found HDAC3 itself is acetylated by CBP at a previously unknown acetylation residue. Our data demonstrated that HDAC3 acetylation is required for gearing down HDAC3 activity and increasing the acetylation of histone proteins to promote the transcription of PTEN. Our findings suggest that HDAC3 acetylation is required for preserving the PTEN expression. The impaired HDAC3 acetylation in CBP LOF mutation lung cancer leads to PTEN loss and consequently promotes tumorigenesis and tumor resistance to chemotherapy. Our findings reveal epigenetic mechanisms of regulating PTEN expression and indicate HDAC3 is a potential target for restoring the tumor suppressor PTEN in CBP LOF mutation cancer.
2024-12-31 | PXD026628 | JPOST Repository
Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. Kinome profiling was performed using the parental line and two PTEN KO clones (5 and 11), treated with DMSO, or treated with 100nM dabrafenib and 10nM trametinib for 1 day or for 7 days. PTEN KO cells showed dramatically increased binding of HER3 and AKT3 compared to wild type. The activation of the SOX10-FOXD3-HER3-AKT axis in PTEN KO cells could be targeted with the ERBB/HER inhibitor neratinib.
2024-04-23 | PXD033921 | Pride
Project description:Lipidomics was performed on prostate tissue from mice aged 17 weeks: WT, Pten-/- and Pten-/- with AMPK gain of function mutation (n=4 per genotype). Lipidomics was also performed on xenograft tissue from mice treated with either Vehicle (n=3) or BI9774 (n=4) to pharmacologically activate AMPK. RAW datafiles were centroided and converted using MSConvert to mzXML format.
2023-03-03 | MSV000091405 | GNPS
Project description:Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene associated with inherited tumour susceptibility conditions, macrocephaly, autism, ataxia, tremor and epilepsy. Functional implications of this protein have been investigated in Parkinson’s and Alzheimer’s diseases. We describe the first patient presented with multifocal demyelinating motor neuropathy in association with a de novo PTEN mutation. The pathogenicity of the mutation was supported by altered expression of several proteins involved in tumorigenesis and fibroblasts showed a reversible defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4,-trisphosphate, suggesting a novel and potentially treatable mechanism for multi-focal demyelinating motor neuropathy.
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Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR-ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR-ABL1 TKIs in CML.
2024-09-15 | GSE275701 | GEO
Project description:Using genetically engineered mice, overexpressing SRC-2, specifically in the prostate epithelium of PTEN heterozygous mice accelerates PTEN mutation induce tumor progression and develops a metastasis-prone cancer. Here we used ChIP-Seq analysis to identify genome-wide SRC-2 binding sites in mouse prostate. Examination of genome-wide SRC-2 binding in mouse prostate by ChIP-seq analysis. Samples were collected from pooled dorsal-lateral prostates of 7 months old-PTEN flox/+; Rosa26-SRC-2 OE/+ mice. Flash frozen tissues were then sent to Active Motif, Inc. for chromatin extraction and followed by immunoprecipitation using anti-SRC-2 antibody (A300-346A, Bethyl Lab., Inc.).
2014-06-30 | E-GEOD-54770 | biostudies-arrayexpress
Project description:Using genetically engineered mice, overexpressing SRC-2, specifically in the prostate epithelium of PTEN heterozygous mice accelerates PTEN mutation induce tumor progression and develops a metastasis-prone cancer. Here we used ChIP-Seq analysis to identify genome-wide SRC-2 binding sites in mouse prostate.
2014-06-30 | GSE54770 | GEO
Project description:Lipidomics was performed on prostate tissue from mice aged 17 weeks: WT, Pten-/- and Pten-/- with AMPK gain of function mutation (n=4 per genotype). Lipidomics was also performed on xenograft tissue from mice treated with either Vehicle (n=3) or BI9774 (n=4) to pharmacologically activate AMPK. RAW datafiles were centroided and converted using MSConvert to mzXML format.
2023-03-03 | MSV000091405 | MassIVE