Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA311261 | ENA |
REPOSITORIES: ENA
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Project description:Resistance to MAP-kinase Pathway Inhibitors in Metastatic Melanoma
| PRJNA311260 | ENA
Project description:The implementations of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of melanoma patients still remains refractory or acquires resistance to these new forms of treatment, illustrating a need for improvement. Here we report that the clinically relevant combination of MAP kinase inhibitors Dabrafenib and Trametinib synergizes with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed the individual therapies. Our study suggests that targeted activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of melanoma patients receiving MAP kinase inhibitors.
2024-06-04 | GSE269008 | GEO
Project description:The implementations of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of melanoma patients still remains refractory or acquires resistance to these new forms of treatment, illustrating a need for improvement. Here we report that the clinically relevant combination of MAP kinase inhibitors Dabrafenib and Trametinib synergizes with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed the individual therapies. Our study suggests that targeted activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of melanoma patients receiving MAP kinase inhibitors.
2024-07-26 | GSE268982 | GEO
Project description:Rapid resistance to BRAF inhibitors in BRAFV600-mutant metastatic melanoma has produced an urgent need for new treatment options. BRAF inhibitor resistance commonly involves reactivation of mitogen-activated protein kinase (MAPK) signaling and yet inhibition of downstream kinases has not circumvented resistance, partly because MAPK is regulated via a complex network of feedback mechanisms that influence pathway rebound. To examine the transcriptome responses of melanoma cells to MAPK inhibition, a panel of 11 BRAFV600-mutant melanoma cell lines were treated with control (DMSO), 100nM dabrafenib alone (i.e BRAF inhibitor monotherapy) or 100nM dabrafenib + 10nM trametinib (i.e combination BRAF + MEK inhibition) for 24h.
2017-09-20 | GSE98314 | GEO
Project description:Systems analysis of adaptive responses to MAP Kinase pathway blockade in BRAF mutant melanoma.
| PRJNA282761 | ENA
Project description:NRAS-mutant melanoma is currently a challenge to treat. This is due to an absence of inhibitors directed against NRAS, along with acquired and adaptive resistance of this tumor type to inhibitors in the MAPK pathway. Inhibitors to MEK (mitogen-activated protein kinase kinase) have shown some promise for this tumor type. In this work we explored the use of MEK inhibitors for NRAS-mutant melanoma, and at the same time investigated the impact of the brain micro-environment, specifically astrocytes, on the response of a melanoma brain metastatic cell line to MEK inhibition. This led to the surprising finding that astrocytes enhance the sensitivity of melanoma tumors to MEK inhibitors (MEKi). We show that MEKi cause an upregulation of the transcription factor ID3, but this is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEK inhibitors, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEK inhibitors against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma.
2022-06-30 | GSE179235 | GEO
Project description:Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to targeted therapy remains a serious clinical issue. To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory. miRNA and gene expression were assessed by microarray analyses of the BRAF inhibitor sensitive melanoma cells A375, IGR37, and 501Mel, as well as on the vemurafenib (PLX4032) - resistant cells A375_XP, IGR37_XP, 501Mel_XP, and dabrafenib (GSK2118436) - resistant cells A375_GP, IGR37_GP, 501Mel_GP. For each cell line the microarray experiment was performed in duplicates.
2017-03-06 | E-MTAB-5511 | biostudies-arrayexpress
Project description:Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to targeted therapy remains a serious clinical issue. To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory. miRNA and gene expression were assessed by microarray analyses of the BRAF inhibitor sensitive melanoma cells A375, IGR37, and 501Mel, as well as on the vemurafenib (PLX4032) - resistant cells A375_XP, IGR37_XP, 501Mel_XP, and dabrafenib (GSK2118436) - resistant cells A375_GP, IGR37_GP, 501Mel_GP. For each cell line the microarray experiment was performed in duplicates.
2017-03-06 | E-MTAB-5510 | biostudies-arrayexpress
Project description:Targeted inhibition of mutated kinases using selective MAP kinase inhibitors in malignant melanoma often results in temporary improvement of the metastatic disease followed by rapid development of resistance. To gain insights in molecular processes that govern resistance, we performed SILAC-based quantitative proteomics profiling of vemurafenib-resistant and -sensitive melanoma cells. Among downregulated proteins in vemurafenib-resistant cell lines we detected multiple proteins involved in cytoskeletal organization and signaling, including the intermediate filament nestin, which was one of the most down-regulated proteins. Previous studies showed that nestin is expressed in various types of solid tumors and its abundance correlates with malignant phenotype of transformed cells. However, the role of nestin in cancer cells with regard to acquired resistance is still poorly understood. We performed CRISPR/Cas9 knockout of the nestin gene (NES) in vemurafenib-sensitive cells and showed that loss of nestin leads to increased cellular proliferation and colony formation upon treatment with BRAF and MEK inhibitors. Moreover, nestin depletion led to increased invasiveness and metalloproteinase activity similar to resistant phenotype of melanoma cells. Finally, phosphoproteome analysis revealed that nestin depletion influenced signaling through integrin and PI3K-Akt-mTOR pathways and led to increased focal adhesion kinase expression and phosphorylation. Taken together, our results reveal that nestin is associated with acquired vemurafenib resistance in melanoma cell lines.
2019-05-14 | PXD010683 | Pride
Project description:Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In 70% of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism.
2023-05-02 | PXD028292 | Pride