RNAseq of A375 melanoma cells and A375 with ARID1A KO in control conditions and treatment with trametinib, vemurafenib or combination
Ontology highlight
ABSTRACT: The experiment aimed to study mechanisms of melanoma drug resistance. ARID1A confers resistance to trametinib and therefore RNAseq was collected alongside other omics data for parental A375 likes, and A375 lines with ARID1A KO, in the presence of no drug, trametinib, vemurafenib or their combination
Project description:RNAseq of A375 melanoma cells and A375 with ARID1A KO in control conditions and treatment with trametinib, vemurafenib or combination
Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. Kinome profiling was performed using the parental line and two PTEN KO clones (5 and 11), treated with DMSO, or treated with 100nM dabrafenib and 10nM trametinib for 1 day or for 7 days. PTEN KO cells showed dramatically increased binding of HER3 and AKT3 compared to wild type. The activation of the SOX10-FOXD3-HER3-AKT axis in PTEN KO cells could be targeted with the ERBB/HER inhibitor neratinib.
Project description:Drug resistant population of PC9(human non-small cell lung cancer) or A375 (human melanoma) cell lines were used for this study. By exome sequencing, we will analyse mutations of cells in drug tolerent state and after drug holiday.
Project description:HOC-7 and MPSC1 are low grade serous ovarian cancer cell lines. These cells was treated with different doses of trametinib in an attempt to identify biomarkers that can be used to predict chemoresponse to this drug. We used microarrays to identify genes induced by trametinib.
Project description:HCT116 cells were treated with with increasing concentrations of trametinib over 2 months. Drug-resistant clones emerged and were cultured in the presence of 30 nmol/L trametinib. These cells exhibited a greater than 10-fold increase in the GI50 for trametinib compared to the parental cell line. RNA-seq of the resistant clone HCT116_R4 versus the parental cells identified differentially expressed genes potentially involved in resistance.
Project description:Identify transcriptionnally and translationally regulated mRNA in melanoma parental and persister cells In this dataset, we include expression data of A375 melanoma drug-naïve parental cells and A375 melanoma persister cells that survived from BRAF and MEK inhibition. The expression data are studied in both total RNA and polysome-bounded RNA.
Project description:To generate drug signatures in human A375 melanoma cell lines. A375 cell line was plated at 4 x 105 cells/mL overnight and treated with ciclopirox or crizotinib at 75% inhibitory concentrations (IC75, determined previously at 72h of treatment) or DMSO (vehicle) for 8h or 24h before harvest.
Project description:Suppression of the insulin/IGF/mTORC1/Ras network ameliorates ageing in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease, and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signalling while trametinib inhibits the Ras/MEK/ERK pathway. We assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. Here we show, that trametinib treatment extended lifespan in both sexes and its combination with rapamycin caused additive prolongation. Combination-treatment reduced liver tumours in both sexes and spleen tumours in males, blocked the age-related increase in brain glucose uptake, and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. Trametinib, which had no obvious side-effects, is therefore geroprotective in mice, and its combination with rapamycin is more effective than either drug alone, making it a candidate for repurposing as a geroprotector in humans.
Project description:To investigate the anti-tumor effect of Rosiglitazone+Trametinib in basal bladder cancer, we tested the drug combination in BBN-induced basal tumor mouse model in vivo and BBN-derived tumor cell line BBN963 in vitro.