Transcriptomic profile of melanoma clinical samples treated with BRAF and MEK- inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA694125 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To analyse the RNA expression differences between melanoma tumour samples treated with BRAF and MEK-inhibitors at different time points
2024-05-03 | GSE165337 | GEO
Project description:Transcriptional profiles of formalin-fixed-paraffin-embedded melanoma metastases including pre-treatment (PRE) and post-treatment (POST) specimens from 50 patients treated with BRAF inhibitors or with BRAF and MEK inhibitors
2022-04-12 | GSE196434 | GEO
Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. SM1 tumors were implanted into C57BL/6 mice. Mice were treated by ACT of pmel-1 splenocytes or C57BL/6 splenocytes as control. Pmel-1 treated mice were additionally treated with either vehicle, dabrafenib, trametinib, or combination of both drugs and control mice were treated with vehicle or combination of both drugs.
2014-12-12 | E-GEOD-64102 | biostudies-arrayexpress
Project description:Melanoma cell lines were assessed for differences in gene expression patterns between the lines sensitive and resistant to BRAF and MEK inhibitor drugs. 22 BRAF-mutant melanoma cell lines were assessed for response to BRAF and MEK inhibitors in a 3 day drug treatment dose response assay. Based on the IC50, 18 lines were found to be responsive to BRAF or MEK inhibition and 4 were resistant. Normalised gene expression data generated from experimental replicate affymetrix arrays was assessed to identify differential patterns of inherent gene expression between the cell lines grouped as drug-responsive or drug-resistant. This were used to idenify specific candidate genes and pathways associated with inherent BRAF/MEK inhibitor drug resistance in melanoma cells.
2015-08-26 | E-GEOD-45558 | biostudies-arrayexpress
Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma.
2014-12-12 | GSE64102 | GEO
Project description:Nearly 30% of all malignant melanomas harbor somatic mutations in NRAS. However, there are currently no effective targeted therapies for this tumor type. The bromodomain and extra terminal domain (BET) family of proteins are transcriptional regulators that serve as scaffolds to facilitate gene transcription by binding to acetylated lysine residues in the N-terminal tail of histones. BET/BRD proteins have emerged as therapeutic targets in a broad range of tumors. We found that BET proteins are overexpressed in NRAS mutant melanoma, and that high levels of BET family member BRD4 are associated with poor patient survival, suggesting that BRD4 plays a key role in melanoma. Consequently, we hypothesized that these epigenetic regulators constitute potential vulnerabilities that can be exploited for melanoma treatment. We found that genetic or pharmacological inhibition of BET/BRD proteins decreases viability and inhibits proliferation of NRAS mutant melanoma cells, as well as BRAF/MEK-inhibitor resistant melanoma cells harboring concurrent BRAF/NRAS mutations. However, BET inhibitors when used as single agents were either cytostatic (in vitro) or ineffective (in vivo). We therefore evaluated combinations that could maximize the efficacy of BET inhibitors in NRAS mutant melanoma. Here we report that co-targeting BET and MEK synergistically restrained tumor growth and significantly prolonged the survival of NRAS-mutant tumor bearing mice. RNA-sequencing and RPPA analysis revealed that co-treatment with BETi/MEKi synergistically downregulated cell cycle regulators and activated caspase-7. This study demonstrates that combined BET and MEK inhibition elicits robust synergistic therapeutic effects and supports the clinical utility of this combination therapy for NRAS mutant melanoma patients.
2018-02-20 | GSE95153 | GEO
Project description:The A375, human BRAFV600E mutant melanoma, cell line (wildtype), two PTEN-null, BRAFV600E cell lines (KO5 and KO11), and PI3K overexpression cells (WT and PI3K H1047R mutant) were treated with small molecule inhibitors (dabrafenib, BRAF inhibitor; trametinib, MEK inhibitor alone and in combination for 0, 1 and 7 days
2019-04-27 | GSE130396 | GEO
Project description:Preclinical and clinical data implicate the transcriptional co-activator YAP1 in resistance to multiple targeted therapies, including BRAF and MEK inhibitors. However, tumor subtypes driven by YAP1 activity and associated vulnerabilities are poorly defined. Here, we show particularly high YAP1 activity in the MITFlow/AXLhigh subset of melanoma cell lines and patient tumors characterized by resistance to MAPK pathway inhibition and broad receptor tyrosine kinase activity. To uncover genetic dependencies of melanoma cells with high YAP1 activity, we used a genome-wide CRISPR/Cas9 functional screen and identified SLC35B2, the 3′-phosphoadenosine-5′-phosphosulfate transporter of the Golgi apparatus, as an essential gene for YAP1-mediated drug resistance. SLC35B2 expression correlates with tumor progression, and its loss decreases heparan sulfate expression, reduces receptor tyrosine kinase activity, and sensitizes resistant melanoma cells to BRAF inhibition in vitro and in vivo. Thus, SLC35B2 is a target in YAP1-driven BRAF mutant melanoma for overcoming drug resistance to MAPK pathway inhibitors.
2022-08-15 | GSE193775 | GEO
Project description:3 BRAF/MEK inhibitor resistance melanoma cells were treated with PAK inhibitor PF3758309 for 48 hr, the cell lysis were analyzed by RPPA profiling by protein array (RPPA)
2017-07-31 | GSE96902 | 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-5510 | biostudies-arrayexpress