Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

32 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of Resistance Genes to BRAF Inhibitor in Melanoma by piggyBac Transposon Activation Mutagenesis Screen

ABSTRACT: Genotype directed anti-cancer therapies such BRAF inhibitor in BRAF mutant melanoma can show remarkable clinical efficacy but resistance limits their benefit. We show that a transposon activation screen efficiently identifies resistance genes to BRAF and captures a number of previously uncharacterized resistance mechanisms, including an E3 ubiquitin ligase NEDD4L and the Hippo pathway effector WWTR1 (TAZ). Resistance can be reversed by combining BRAF inhibition with tyrosine kinase inhibitors as observed previously for other resistance genes. Moreover, an integrative analysis of several gain- and loss-of-function genetic screens performed in the same context reveals smaller functional diversity of resistance mechanisms to MAPK inhibition than suggested by the broad range of resistance genes identified, implying common therapeutic strategies. A375 cells with lentiviral vector controls or WWTR1 cDNA plasmid.

ORGANISM(S): Homo sapiens

SUBMITTER: Cyril Benes

PROVIDER: E-GEOD-73470 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Identification of Resistance Genes to BRAF Inhibitor in Melanoma by piggyBac Transposon Activation Mutagenesis Screen

Project description:Genotype directed anti-cancer therapies such BRAF inhibitor in BRAF mutant melanoma can show remarkable clinical efficacy but resistance limits their benefit. We show that a transposon activation screen efficiently identifies resistance genes to BRAF and captures a number of previously uncharacterized resistance mechanisms, including an E3 ubiquitin ligase NEDD4L and the Hippo pathway effector WWTR1 (TAZ). Resistance can be reversed by combining BRAF inhibition with tyrosine kinase inhibitors as observed previously for other resistance genes. Moreover, an integrative analysis of several gain- and loss-of-function genetic screens performed in the same context reveals smaller functional diversity of resistance mechanisms to MAPK inhibition than suggested by the broad range of resistance genes identified, implying common therapeutic strategies.

2016-07-01 | GSE73470 | GEO

A four-arm study of A375 melanoma cell line-derived xenograft tumors in NSG mice treated with Vemurafenib and CB839

Project description:Melanoma is a rare but deadly form of skin cancer, which is often treated with BRAF inhibitors such as Vemurafenib (referred to as PLX4032). Whilst Vemurafenib prolongs the survival of patients, BRAF inhibitor resistance inevitably occurs in most cases. Previous studies demonstrated that metabolic rewiring occurs in BRAF inhibitor resistance and causes dependence on glutamine. To investigate whether this vulnerability could be exploited with clinically relevant drugs, we used the BRAF inhibitor, Vemurafenib, and the glutaminase imhibitor, CB839 to treat A375-derived melanoma xenografted tumors. We showed that whilst CB839 did not significantly affect the growth of A375-derived tumors compared to those given a vehicle, the addition of CB839 to Vemurafenib treatment had a significant anti-tumor effect. Tumors were taken at the endpoint (Max tumor length 15mm) from the 6 mice in each treatment group and cut into fragments and stored in RNAlater for RNAseq analysis. RNA extraction was performed on 1-3 fragments per tumor to make up 200-300mg of tissue.

2023-04-07 | E-MTAB-12811 | biostudies-arrayexpress

RNA-seq data set of EGFR mutant human non-small cell lung cancer cell lines PC9, HCC827, HCC4006 after NF2 knockout, YAP1 or WWTR1 overexpression or osimertinib treatment

Project description:Experiment was designed to study the effect of Hippo pathway on osimertinib resistance in non-small cell lung cancer cell lines. The specific comparisons investigated were: PC-9: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE, EV DMSO treated vs EV osimertinib treated HCC827: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE,EV DMSO treated vs EV osimertinib treated HCC4006: NTC vs NF2 KO, EV vs YAP1 OE, EV vs WWTR1 OE, EV DMSO treated vs EV osimertinib treated

2024-07-01 | E-MTAB-13831 | biostudies-arrayexpress

Ezrin inhibition overcomes acquired resistance to vemurafenib in BRAFV600E-mutated colon cancer and melanoma cells in vitro

Project description:In spite of the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.

2023-08-29 | PXD042499 | Pride

Whole Genome Sequence Analysis of Mycobacterium tuberculosis Strains from Patients in Campania Region

Project description:Tuberculosis (TB) is one of the deadliest infectious disorders in the world. To effectively TB manage, an essential step is to gain insight into the lineage of Mycobacterium tuberculosis (MTB) strains and the distribution of drug resistance. Although the Campania region is declared a cluster area for the infection, to contribute to the effort to understand TB evolution and transmission, still poorly known, we have generated a dataset of 159 genomes of MTB strains, from Campania region collected during 2018-2021, obtained from the analysis of whole genome sequence data. The results show that the most frequent MTB lineage is the 4 according for 129 strains (81.11%). Regarding drug resistance, 139 strains (87.4%) were classified as multi susceptible, while the remaining 20 (12.58%) showed drug resistance. Among the drug-resistance strains, 8 were isoniazid-resistant MTB (HR-MTB), 7 were resistant only to one antibiotic (3 were resistant only to ethambutol and 3 isolate to streptomycin while one isolate showed resistance to fluoroquinolones), 4 multidrug-resistant MTB, while only one was classified as pre-extensively drug-resistant MTB (pre-XDR). This dataset expands the existing available knowledge on drug resistance and evolution of MTB, contributing to further TB-related genomics studies to improve the management of TB infection.

2023-11-17 | E-MTAB-13058 | biostudies-arrayexpress

The ETS transcription factor ELF5 modulates estrogen action in breast cancer via participation in FOXA1-ER driven transcription.

Project description:The ETS transcription factor ELF5 drives mammary alveolar development in preparation for lactation by forcing differentiation within the progenitor cell population. In luminal A breast cancer, early disease progression is predicted by high levels of ELF5, and in preclinical models elevated ELF5 is associated with its two key features, the acquisition of resistance to endocrine therapy and increased metastasis. We first created an MCF7 cell line with doxycycline-inducible ELF5 and then examined with ChIP-seq differences in genomic binding of FOXA1, ER and H3K4me3 upon doxycycline treatment, compared to vehicle. In addition we performed RNA-seq experiments to examine changes in gene expression upon induction of ELF5 expression. Here we demonstrate that ELF5 binding overlaps with FOXA1 and ER at enhancers and promoters, and when elevated causes FOXA1 and ER to bind to new regions of the genome involved in resistance to endocrine therapy. RNA-seq demonstrated that these changes altered gene expression to diminish estrogen influence, and that ELF5 regulated the expression of ER transcription-complex genes. These data show that ELF5 modulated estrogen-driven transcription in breast cancer by directing FOXA1 and ER to new genomic locations, and by interaction with, and regulation of, members of the ER transcriptional complex. This provides a mechanistic basis for the influence of ELF5 on the progression of luminal breast cancer to endocrine insensitivity.

2020-01-06 | E-MTAB-7641 | biostudies-arrayexpress

Transcriptome analysis of long term potentiation in rat dentate gyrus

Project description:In vivo high frequency stimulated of left dentate gyrus was performed on anaesthetised rats followed by RNA-seq to study long-term potentiation. Both left and right dentate gyrus was collected, sequenced and compared against each other for naive rats and for rats 30 min, 2 hours, and 5 hours post-HFS.

2015-10-20 | E-MTAB-3375 | biostudies-arrayexpress

Changes in the coding/non-coding transcriptome and DNA methylome that define the Schwann cell repair phenotype after nerve injury

Project description:Schwann cell (Büngner) repair cells play a critical role in orchestrating nerve repair after injury, but the reprogramming process that generates them is poorly understood. We present the first combined whole genome coding and non-coding RNA and CpG methylation study after nerve injury. We show that genes involved in epithelial to mesenchymal transition are enriched in repair cells and we identify long non-coding RNAs in Schwann cells. We demonstrate that the AP-1 transcription factor c-Jun regulates the expression of certain micro RNAs in repair cells, in particular miR-21 and miR-34. Surprisingly, changes in CpG methylation are limited in injury, unlike development, and restricted to specific locations, such as enhancer regions of novel Schwann cell specific genes, such as Nedd4l, and near to local enrichment of AP-1 motifs. These epigenetic changes significantly broaden our understanding of Schwann cell reprogramming in peripheral nervous system tissue repair. To identify epigenetic regulators underlying successful nerve regeneration we generated RNA-Seq, small-RNA-Seq and whole genome bisulfite sequencing libraries for uninjured nerve versus three and/or seven day post nerve transection sciatic nerves of adult C57BL/6J mice crush.

2017-08-30 | E-MTAB-5633 | biostudies-arrayexpress

RNA-Guided Human Gene Activation by Cas9/CRISPR-Based Engineered Transcription Factors

Project description:Synthetic transcription factors can be applied in many areas of biotechnology, medicine, and basic research. In contrast to current methods based on engineering new DNA-binding proteins, we show that Cas9 fused to a transcriptional activation domain can be targeted by combinations of guide RNA molecules to induce the expression of endogenous human genes. This simple approach for targeted gene activation circumvents the need for engineering new proteins and will enable widespread synthetic gene regulation. HEK293T cells were transfected with plasmid expressing Cas9-VP64 fusion protein and a guide RNA. As a control, empty guide RNA was transfected. Gene expression was then measured using mRNA-seq, and differential expression calculated using DESeq. All experiments were performed in biological duplicates or triplicates.

2013-07-25 | E-GEOD-47114 | biostudies-arrayexpress

The lncRNA TAZ-AS202 promotes lung cancer progression through stabilization of the E2F1 transcription factor and activation of Ephrin signaling

Project description:Silencing of TAZ (WWTR1) and lncRNA TAZ-AS202 (WWTR1-AS1-202) by siRNA transfection on A549 cell line of lung cancer

2023-12-07 | E-MTAB-12507 | biostudies-arrayexpress