Gene copy number variation profiling by microarray
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE168603 | GEO | 2021/03/23
REPOSITORIES: GEO
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Project description:Here, we investigate gene expression response of the BRAFV600E mutant cell line COLO205 to the MEK inhibitor selumetinib / AZD6244 / ARRY-142886. Although selumetinib causes long term G1 arrest, we observe cells stochastically entering the cell cycle without re-activation of ERK and initiation of a normal proliferative gene expression programme. Genes encoding DNA replication and repair factors are downregulated during G1 arrest, but many of these are transiently induced when cells escaping arrest enter S and G2. Nonetheless, mRNAs encoding key DNA replication factors including the MCM replicative helicase complex, PCNA and TIPIN remain at very low abundance.
2021-09-12 | GSE183859 | GEO
Project description:Here, we investigate gene expression response of the BRAFV600E mutant cell line COLO205 to the MEK inhibitor selumetinib / AZD6244 / ARRY-142886. Although selumetinib causes long term G1 arrest, we observe cells stochastically entering the cell cycle without re-activation of ERK and initiation of a normal proliferative gene expression programme. Genes encoding DNA replication and repair factors are downregulated during G1 arrest, but many of these are transiently induced when cells escaping arrest enter S and G2. Nonetheless, mRNAs encoding key DNA replication factors including the MCM replicative helicase complex, PCNA and TIPIN remain at very low abundance.
2021-03-23 | GSE168602 | GEO
Project description:Here we apply single cell bisulfite sequencing to detect epigenetic and genetic changes that occur in BRAF V600E cells that escape G1 arrest and return to the cell cycle during treatment with the MEK inhibitor selumetinib. We detect no major changes in DNA methylation, but find that cells in G2 are enriched in large amplifications and deletions that we ascribe to abnormal mitotic chromosome segregation.
2022-09-11 | GSE212899 | GEO
Project description:Combining direct anti-tumor effects with targeting of tumor microenvironment is an attractive strategy that may lead to more effective therapies for advanced melanoma. Here, we tested whether association of TRAIL with co-targeting of MEK and PI3K/mTOR, or with MEK blockade, could have synergistic anti-melanoma activity mediated not only by induction of tumor cell death, but also by effects on the tumor microenvironment. Drug interaction analysis by the Chou-Talalay approach in a panel of 21 melanoma cell lines indicated that strong synergism could be achieved by association of the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor NPV-BEZ235 and TRAIL, as well as by the AZD6244/TRAIL combination. Synergism was observed on most tumors including TRAIL- or inhibitor-resistant melanomas, irrespective of the BRAF, NRAS, p53 and PTEN status, and was explained by enhanced induction of caspase-dependent melanoma apoptosis. The AZD/BEZ/TRAIL and AZD/TRAIL combinatorial treatments induced strong modulation of key apoptosis regulators along the extrinsic and intrinsic cell death pathways, including c-FLIP down-regulation, caspase-8 cleavage, BIMs and BAXa upregulation, clusterin and Mcl-1 inhibition, enhanced mitochondrial depolarization, suppression of inhibitors of apoptosis c-IAP1, c-IAP2, XIAP and Apollon, and caspase 3/7 activation. In an in vivo model, the AZD6244/TRAIL combinatorial treatment induced highly significant growth inhibition of a TRAIL-resistant tumor associated not only with melanoma cell death, but even with suppression of pro-angiogenic molecules HIF1a, VEGFa, IL-8 and TGFb1, and with inhibition of tumor angiogenesis. These results provide a proof of principle supporting the rationale for combinatorial treatments with synergistic anti-melanoma activity based on direct and indirect anti-tumor effects. The human melanoma cell line Me13 was established in our laboratory from a surgical specimen. Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 10% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37°C in a water-saturated atmosphere of 5% CO2 in air. 3x10^6 cells were seeded in 75 cm2 flasks; after 24 hours, cells were left untreated or treated with Selumetinib (Selleck Chemicals, Houston, TX) at 0.1 micromol/L, NVP-BEZ-235 (Selleck Chemicals, Houston, TX) at 0.1 micromol/L and sTRAIL (AdipoGen) at 25ng/ml as single drugs or in combination for 8 hours. Each treatment or combination was performed in triplicate. At the end of treatment, cells were collected and RNA extracted.
2014-10-08 | E-GEOD-55050 | biostudies-arrayexpress
Project description:CGH profiling of M249 melanoma cell line treated with step-wise increasing Vemurafenib and Selumetinib to develop resistance (VSR). The resistance mechanims was through BRAF amplification in double minute (DM) format. The control cell line is untreated M249.
2021-12-20 | GSE153526 | GEO
Project description:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al. A375 and 16R6-4 (an A375 derived GSK2118436 resistance clone) were treated for 24 hours with 0.1 micromolar GSK2118436, 1 micromolar GSK2118436, 0.01 micromolar GSK1120212, 0.1 micromolar GSK2118436 + 0.01 micromolar GSK1120212, or 1 micromolar GSK2118436 + 0.01 micromolar GSK1120212.
2012-02-01 | E-GEOD-35230 | biostudies-arrayexpress
Project description:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al.
2012-02-01 | GSE35230 | GEO
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 use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a BRAFV600E mutation. Unfortunately, the majority of patients eventually develop drug-resistant disease through a variety of mechanisms. We previously described the creation of a panel of spontaneously BRAFi/MEKi-resistant A375 melanoma cells that displayed multiple different resistance mechanisms arising within the same parental cell population. These resistance mechanisms include (i) rearrangements in the BRAF gene resulting in truncation of the N-terminal regulatory domain or tandem duplication of the BRAF kinase domain, (ii) loss of Ras-GAP NF1, and (iii) a slower arising form of drug resistance associated with a more spread cell morphology and increased phospho-MEK S298, a characteristic of cells with increased Rac1 signaling. We provide here comprehensive gene expression profiling for this panel of cell lines. Rac1 mutation, particularly the P29S variant, is common in melanoma patients, where it is associated with BRAFi/MEKi resistance and worse clinical outcomes. Here we delineate mechanisms of Rac1-driven MAPKi-resistance and identify strategies to inhibit the growth of this class of cutaneous melanomas. We find that Rac1-driven melanomas manifest pleiotropic resistance mechanisms including (i) reduced dependence on BRAF/MEK, (ii) activation of alternative MAPK pathways utilizing Jun kinase and p38 MAP kinase, and (iii) a partial reliance on YAP/TAZ signaling. Importantly, although Rac1-driven melanoma cells display reduced dependence on BRAF/MEK, they are not completely ERK-independent. Moreover, the presence of activated Rac1 appears to create a dependency on focal adhesion kinase (FAK) signaling in undifferentiated melanoma cells. As a result, we find that, despite the pleiotropic mechanisms of Rac1-driven MAPKi resistance, combined inhibition of MEK and FAK with avutometinib plus defactinib is a promising approach for suppressing the growth of Rac1-driven cells. Thus, the avutometinib plus defactinib combination, which is currently being investigated for brain metastatic cutaneous melanoma may also have utility against Rac1-driven MAPKi-resistance in heavily pre-treated, advanced disease.
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Project description:The experiment investigates transcriptional response of BRAF-mut Colo205 cancer cells following treatment for 24h or 72h with BRAF-inhibitor vemurafenib compared to control cells on a single cell level.
2021-07-19 | E-MTAB-9890 | biostudies-arrayexpress