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Coordinated transcriptional and catabolic programs support iron dependent adaptation to RAS-MAPK pathway inhibition in pancreatic cancer [ChIP-Seq]

ABSTRACT: In this study, human pancreatic ductal adenocarcinoma cells lines (KP4, MiaPaca2) were treated with the MEK inhibitor, Trametinib or DMSO for 48hrs prior to RNA-seq profiling to evaluate significant gene expression changes associated with MEK inhibition. To assess the role of transcription factors MYC and TFE3 in regulation of gene expression changes associated with MEK inhibition, we performed chromatin immunoprecipitation using antibodies against c-MYC and TFE3 in KP4 cells following 48hrs of Trametinib or DMSO treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206268 | GEO | 2022/07/06

REPOSITORIES: GEO

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Coordinated transcriptional and catabolic programs support iron dependent adaptation to RAS-MAPK pathway inhibition in pancreatic cancer [RNA-Seq]

Project description:In this study, human pancreatic ductal adenocarcinoma cells lines (KP4, MiaPaca2) were treated with the MEK inhibitor, Trametinib or DMSO for 48hrs prior to RNA-seq profiling to evaluate significant gene expression changes associated with MEK inhibition. To assess the role of transcription factors MYC and TFE3 in regulation of gene expression changes associated with MEK inhibition, we performed chromatin immunoprecipitation using antibodies against c-MYC and TFE3 in KP4 cells following 48hrs of Trametinib or DMSO treatment.

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Coordinated transcriptional and catabolic programs support iron dependent adaptation to RAS-MAPK pathway inhibition in pancreatic cancer

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2022-06-16 | MSV000089676 | MassIVE

Cordinated transcriptional and catabolic programs support iron dependent adaptation to RAS-MAPK pathway inhibition in pancreatic cancer_2

Project description:Whole cell proteomics of human pancreatic ductal adenocarcinoma cells - KP4 - treated for 48hrs with DMSO or 100nM Trametinib. Cell pellets were collected from n=3 biological replicates per condition. The samples were labeled with TMT reagents and combined together, fractionated into 96 fractions, and then pooled back into 24 fractions. 12 of the fractions were run and correspond to the 12 uploaded files.

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Human basal-like breast cancer cell line HCC1143 treated with BET inhibitor JQ1 in combination with MEK inhibitor Trametinib or PI3K/mTOR inhibitor BEZ235

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.

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Capicua-dependent transcriptional changes in human cancer cell lines treated with trametinib

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.

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Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex (ChIP-seq)

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Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex (DNA methylation)

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Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex (Exome-seq)

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Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex (RNA-seq)

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Melanoma cell lines treated with dabrafenib ± trametinib

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.

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