Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1063706 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27491086_1.fastq.gz | Fastqsanger.gz | |||
| SRR27491086_2.fastq.gz | Fastqsanger.gz | |||
| SRR27491087_1.fastq.gz | Fastqsanger.gz | |||
| SRR27491087_2.fastq.gz | Fastqsanger.gz | |||
| SRR27491088_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 16 |
Similar Datasets
Project description:Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient or tumor specific variations, we constructed cell line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting ppERK and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.
2024-09-03 | PXD047912 | Pride
Project description:Purpose: To identify new targets in melanoma for targeted treatment based on a mutational analysis of melanoma cell lines and subsequent individualized treatment combinations. Experimental Design: A series of 57 melanoma cell lines (mostly short-term cultures) are analyzed for their mutation pattern based on a mutation panel of 83 genes selected from the most abundant mutations (more than 5 % of samples). Of these, 28 cell lines are treated with small molecule inhibitors either as single-agent or combination therapy. Most effective therapies are estimated by Chou Talaley method, applied to multiple drug treatments, based on growth characteristics of melanoma cells during life-cell imaging. Results: In a number of cell lines, combination treatment showed better treatment response rates than monotherapy. BRAFi and an inhibitor of a further pathway is more efficient to induce an anti-proliferative effect than the standard therapy with a BRAFi-MEKi combination. Among these are PI3K/mTOR inhibitor apitolisib either together with a BRAFi or as triple combination with BRAFi/MEKi. A combination of BRAFi and CDK4/6 inhibitor palbociclib also showed significant synergy. The most promising drug combinations in NRASmut cell lines is a triple combination of MEKi, ERKi and and PI3K/mTOR apitolisib, or a combination of MEKi, apitolisib and aurora A kinase inhibitor alisertib. Transcriptomic analysis showed that BRAF and NRAS mutant cell lines could be differentiated by ARHGAP42 and DLD expression, both higher expressed in BRAFmut cell lines, and ARHGAP42 being a putative new target for BRAFmut melanoma cells. Conclusion: Combination treatment of melanoma cells with individual drug combinations based on mutational patterns are sometimes more effective than monotherapy or classical double-agent therapy and may thereby replace classical treatment approaches.
2025-01-24 | GSE287916 | GEO
Project description:Tumor heterogeneity and therapy resistance are hallmarks of pancreatic ductal adenocarcinoma (PDAC). Emerging evidence supports treatment-induced resistance to be a multifactorial process mediated by cellular plasticity involving epigenetic regulation. Here, we used a multi-omics approach to analyze in detail molecular mechanisms underlying MEK inhibitor (MEKi) resistance. Therefore, we characterized different cell stages (parental, MEKi resistant, reverted after different passages of drug withdrawal) in primary cell lines derived from a genetic PDAC mouse model, thereby minimizing inter-individual heterogeneity that could distort genome-wide analyses.
2024-01-26 | PXD018093 | Pride
Project description:Tumor heterogeneity and therapy resistance are hallmarks of pancreatic ductal adenocarcinoma (PDAC). Emerging evidence supports treatment-induced resistance to be a multifactorial process mediated by cellular plasticity involving epigenetic regulation. Here, we used a multi-omics approach to analyze in detail molecular mechanisms underlying MEK inhibitor (MEKi) resistance. Therefore, we characterized different cell stages (parental, MEKi resistant, reverted after different passages of drug withdrawal) in primary cell lines derived from a genetic PDAC mouse model, thereby minimizing inter-individual heterogeneity that could distort genome-wide analyses.
2024-01-29 | GSE146348 | GEO
Project description:Oncogenic KRAS signaling is a hallmark of pancreatic ductal adenocarcinoma (PDAC), a lethal malignancy with few treatment options. A major roadblock in deploying therapies targeting the KRAS-MAPK pathway is the rapid emergence of resistant cancer cells. However, molecular mechanisms underlying adaptive targeted therapy resistance in PDAC are poorly understood. Here we find SETD5 (SET domain containing 5) as a major epigenetic driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is identified in a genetic screen of annotated methyltransferases that mediate MEKi toxicity in PDAC cells. SETD5 expression is induced upon PDAC cells and tumors acquring MEKi-resistance and SETD5 deletion restores vulnerability of refractory PDAC to MEKi therapy in mouse models and patient-derived xenografts (PDX). SETD5 lacks intrinsic histone methyltransferase activity and rather scaffolds a distinct corepressor complex that regulates HDAC3 and G9a catalytic behaviors to couple selective deacetylation with methylation of histone H3 at lysine 9 (H3K9). Gene silencing by the SETD5 complex regulates a network of known drug resistance pathways to reprogram cellular responses to MEKi, a resistance program disrupted by G9a and HDAC3 blockade. Combinatorial pharmacological targeting of MEK1/2, G9a, and HDAC3 results in sustained tumor growth inhibition in murine and human models of PDAC. Together, our work uncovers SETD5 as a master epigenetic regulator of acquired MAPK-pathway therapy resistance and suggests an efficacious clinical path for MEKi in PDAC.
2020-05-06 | GSE142046 | GEO
Project description:To understand the mechanisms involved in synergy to PI3Ki + MEKi treatment, we performed a global phosphoproteomics analysis in 3 different cancer cell lines treated with a MEK inhibitor (Trametinib) and a PI3K inhibitor (Pictilisib) at 500 nM individually or in combination for one hour.
2022-04-25 | PXD018873 | Pride
Project description:comparative expression between stromal MS5 cells treated with (MS5_PD18) or without (MS5_DMSO) MEKi Stromal MS5 cells were treated during 7 days with MEKi (1µM) or diluent
2013-05-01 | E-GEOD-43623 | biostudies-arrayexpress
Project description:KRAS inhibitors have demonstrated exciting pre-clinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KRASG12D, p53 mutant, murine PDAC-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intra-tumoral CD8+ T cells without durable responses. scRNA-sequencing revealed an increase in inflammatory cancer associated fibroblasts (iCAFs), M2 macrophages, and a decreased dendritic cell quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor free mice with established immune memory. Our data suggests that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.
2024-04-22 | GSE264527 | GEO