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 |
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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: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: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.
2024-01-29 | GSE146348 | GEO
Project description:Direct targeting of KRAS to inhibit the MAPK cascade is poised to transform the therapeutic landscape of pancreatic ductal adenocarcinoma (PDAC). However, analyses of PDAC samples from patients treated with KRASG12C inhibitors have revealed secondary mutations restoring MAPK signaling and promoting epithelial-to-mesenchymal transition (EMT) as key mechanisms of acquired resistance. Here, we show that human PDAC specimens and patient-derived cell lines treated with the ERK inhibitor ulixertinib display upregulation of EMT-associated and inflammatory gene programs, particularly those linked to the interferon response. Using the GeneRep-nSCORE computational framework to reconstruct and rank regulatory networks enriched in ERKi and KRASi-resistant PDAC cells, we identified TRIM22, an interferon-inducible E3 ubiquitin ligase, as a critical mediator of EMT and treatment resistance. Mechanistically, TRIM22 promotes proteasomal degradation of IκBα, leading to activation of NF-κB signaling, a known driver of EMT. Notably, we identify TACSTD2, encoding Trophoblast Cell Surface Antigen 2 (TROP2), as an NF-κB target gene upregulated following EMT. Functionally, combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan significantly suppressed the growth of PDAC patient-derived xenografts. Together, our work identifies TRIM22 as a molecular link between interferon signaling and EMT and reveals TROP2 as a druggable vulnerability to sustain the therapeutic efficacy of KRAS-MAPK pathway inhibitors.
2026-03-25 | GSE303106 | 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:Direct targeting of KRAS to inhibit the MAPK cascade is poised to transform the therapeutic landscape of pancreatic ductal adenocarcinoma (PDAC). However, analyses of PDAC samples from patients treated with KRASG12C inhibitors have revealed secondary mutations restoring MAPK signaling and promoting epithelial-to-mesenchymal transition (EMT) as key mechanisms of acquired resistance. Here, we show that human PDAC specimens and patient-derived cell lines treated with the ERK inhibitor ulixertinib display upregulation of EMT-associated and inflammatory gene programs, particularly those linked to the interferon response. Using the GeneRep-nSCORE computational framework to reconstruct and rank regulatory networks enriched in ERKi and KRASi-resistant PDAC cells, we identified TRIM22, an interferon-inducible E3 ubiquitin ligase, as a critical mediator of EMT and treatment resistance. Mechanistically, TRIM22 promotes proteasomal degradation of IκBα, leading to activation of NF-κB signaling, a known driver of EMT. Notably, we identify TACSTD2, encoding Trophoblast Cell Surface Antigen 2 (TROP2), as an NF-κB target gene upregulated following EMT. Functionally, combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan significantly suppressed the growth of PDAC patient-derived xenografts. Together, our work identifies TRIM22 as a molecular link between interferon signaling and EMT and reveals TROP2 as a druggable vulnerability to sustain the therapeutic efficacy of KRAS-MAPK pathway inhibitors.
2026-03-25 | GSE303105 | GEO
Project description:Direct targeting of KRAS to inhibit the MAPK cascade is poised to transform the therapeutic landscape of pancreatic ductal adenocarcinoma (PDAC). However, analyses of PDAC samples from patients treated with KRASG12C inhibitors have revealed secondary mutations restoring MAPK signaling and promoting epithelial-to-mesenchymal transition (EMT) as key mechanisms of acquired resistance. Here, we show that human PDAC specimens and patient-derived cell lines treated with the ERK inhibitor ulixertinib display upregulation of EMT-associated and inflammatory gene programs, particularly those linked to the interferon response. Using the GeneRep-nSCORE computational framework to reconstruct and rank regulatory networks enriched in ERKi and KRASi-resistant PDAC cells, we identified TRIM22, an interferon-inducible E3 ubiquitin ligase, as a critical mediator of EMT and treatment resistance. Mechanistically, TRIM22 promotes proteasomal degradation of IκBα, leading to activation of NF-κB signaling, a known driver of EMT. Notably, we identify TACSTD2, encoding Trophoblast Cell Surface Antigen 2 (TROP2), as an NF-κB target gene upregulated following EMT. Functionally, combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan significantly suppressed the growth of PDAC patient-derived xenografts. Together, our work identifies TRIM22 as a molecular link between interferon signaling and EMT and reveals TROP2 as a druggable vulnerability to sustain the therapeutic efficacy of KRAS-MAPK pathway inhibitors.
2026-03-25 | GSE303323 | GEO
Project description:Direct targeting of KRAS to inhibit the MAPK cascade is poised to transform the therapeutic landscape of pancreatic ductal adenocarcinoma (PDAC). However, analyses of PDAC samples from patients treated with KRASG12C inhibitors have revealed secondary mutations restoring MAPK signaling and promoting epithelial-to-mesenchymal transition (EMT) as key mechanisms of acquired resistance. Here, we show that human PDAC specimens and patient-derived cell lines treated with the ERK inhibitor ulixertinib display upregulation of EMT-associated and inflammatory gene programs, particularly those linked to the interferon response. Using the GeneRep-nSCORE computational framework to reconstruct and rank regulatory networks enriched in ERKi and KRASi-resistant PDAC cells, we identified TRIM22, an interferon-inducible E3 ubiquitin ligase, as a critical mediator of EMT and treatment resistance. Mechanistically, TRIM22 promotes proteasomal degradation of IκBα, leading to activation of NF-κB signaling, a known driver of EMT. Notably, we identify TACSTD2, encoding Trophoblast Cell Surface Antigen 2 (TROP2), as an NF-κB target gene upregulated following EMT. Functionally, combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan significantly suppressed the growth of PDAC patient-derived xenografts. Together, our work identifies TRIM22 as a molecular link between interferon signaling and EMT and reveals TROP2 as a druggable vulnerability to sustain the therapeutic efficacy of KRAS-MAPK pathway inhibitors.
2026-03-25 | GSE303051 | GEO
Project description:Direct targeting of KRAS to inhibit the MAPK cascade is poised to transform the therapeutic landscape of pancreatic ductal adenocarcinoma (PDAC). However, analyses of PDAC samples from patients treated with KRASG12C inhibitors have revealed secondary mutations restoring MAPK signaling and promoting epithelial-to-mesenchymal transition (EMT) as key mechanisms of acquired resistance. Here, we show that human PDAC specimens and patient-derived cell lines treated with the ERK inhibitor ulixertinib display upregulation of EMT-associated and inflammatory gene programs, particularly those linked to the interferon response. Using the GeneRep-nSCORE computational framework to reconstruct and rank regulatory networks enriched in ERKi and KRASi-resistant PDAC cells, we identified TRIM22, an interferon-inducible E3 ubiquitin ligase, as a critical mediator of EMT and treatment resistance. Mechanistically, TRIM22 promotes proteasomal degradation of IκBα, leading to activation of NF-κB signaling, a known driver of EMT. Notably, we identify TACSTD2, encoding Trophoblast Cell Surface Antigen 2 (TROP2), as an NF-κB target gene upregulated following EMT. Functionally, combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan significantly suppressed the growth of PDAC patient-derived xenografts. Together, our work identifies TRIM22 as a molecular link between interferon signaling and EMT and reveals TROP2 as a druggable vulnerability to sustain the therapeutic efficacy of KRAS-MAPK pathway inhibitors.
2026-03-25 | GSE303104 | GEO