Gene expression changes induced by the BET inhibitor GSK525762 and/or the MEK inhibitor trametinib in cancer cell lines.
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PROVIDER: PRJNA445465 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptional changes were analyzed in two colorectal cancer, two pancreatic cancer, and one small cell lung cancer cell line following treatment with the BET inhibitor GSK525762 and/or the MEK inhibitor trametinib using Affymetrix Human Genome U133 Plus 2.0 Arrays.
2018-04-20 | GSE112282 | GEO
Project description:The goal of this experiment was to understand the changes in gene expression in the human basal-like breast cancer cell line HCC1143 following treatment with the MEK inhibitor Trametinib (T), PI3K/mTOR inhibitor BEZ235 (B), the BET inhibition JQ1 (JQ), Trametinib + JQ1 (TJ), or BEZ235 + JQ1(BJ), compared to a DMSO control (D). Samples were treated for 72hr and run in triplicate.
2017-05-30 | GSE82032 | GEO
Project description:We performed a genome-scale CRISPR screen in a KRAS-mutant pancreatic cancer cell line treated with the MEK inhibitor trametinib, and found that loss of the transcriptional repressor CIC confers resistance to MEK inhibition. We determined that CIC loss also confers resistance to MEK or BRAF inhibition in lung cancer, colorectal cancer, and melanoma cell lines with mutant RAS or BRAF. CIC is a transcriptional repressor that is phosphorylated and inhibited by the MAPK pathway. We hypothesized that inhibition of the MAPK pathway would lead to activation of CIC and repression of CIC target genes. Loss of CIC would therefore restore expression of these genes, conferring drug resistance. To identify the relevant CIC target genes that mediate trametinib resistace, we generated 4 Cas9-expressing cell lines from different lineages and with different RAS or RAF mutations, and generated control (gGFP) or CIC-knockout (gCIC) cell lines. We treated cells with DMSO or trametinib for 24 hours, and performed NRA-seq. We found that trametinib treatment reduces expression of at least one member of the PEA3 family of ETS transcription factors (ETV1, ETV4, and ETV5) in all cell lines assessed, and that loss of CIC results in maintained expression of these genes despite MEK inhibition. We further validated that ETV1, 4, and 5 expression was necessary for resistance mediated by CIC loss; and that ETV1, 4, or 5 expression was sufficient to confer trametinib resistance.
2017-05-31 | GSE78519 | GEO
Project description:Purpose: Study the changes in the transcriptome of metastatic melanoma PDX cells upon combination treatment with AURKA and MEK inhibitors Methods: RNAseq analysis of melanoma PDX cells treated with AURKA inhibitor Alisertib (500nM) and MEK inhibitor trametinib (100nM) for 72 h
2023-07-07 | GSE207645 | 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:Mutation or deletion of Neurofibromin (NF1), an inhibitor of RAS signaling, frequently occurs in epithelial ovarian cancer (EOC), supporting therapies that target downstream RAS effectors, such as the RAF-MEK-ERK pathway. However, no comprehensive studies have been carried out testing the efficacy of MEK inhibition in NF1-deficient EOC. Here, we performed a detailed characterization of MEK inhibition in NF1-deficient EOC cell lines using kinome profiling and RNA sequencing. Our studies showed MEK inhibitors were ineffective at providing durable growth inhibition in NF1-deficient cells due to kinome reprogramming. MEKi-mediated destabilization of FOSL1 resulted in induced expression of RTKs and their downstream RAF and PI3K signaling overcoming MEKi therapy. MEKi synthetic enhancement screens identified BRD2 and BRD4 as integral mediators of the MEKi-induced RTK signatures. Inhibition of BET proteins using BET bromodomain inhibitors (BETi) blocked MEKi-induced RTK reprogramming, indicating BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC.
2019-05-17 | GSE127886 | 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:MEK inhibitor trametinib induces SMS-CTR cell differentiation and up-regulates CASZ1 expression. We identified genome-wide binding sites of CASZ1 in differentiated SMS-CTR cells.
2019-12-26 | GSE126143 | 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