Screen1 VOA6406gain-of-function meki-resistance data
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE213580 | GEO | 2022/09/21
REPOSITORIES: GEO
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Project description:Background: Neurofibromatosis type 1 (NF1) is a genetic condition predisposing children to fracture pseudarthroses. MEK inhibitors are FDA-approved or under study for the treatment of malignant pathologies associated with NF1, though their potential to treat pseudarthrosis is largely unknown. Methods: Primary cells cultured from control bone (i.e., iliac crest) or fracture pseudarthroses from children with NF1 were treated with vehicle or the MEK inhibitors trametinib or selumetinib. Gene expression was evaluated by transcriptome sequencing (RNAseq), and activation of the downstream signaling pathway was evaluated by western blotting. Results were replicated in an independent cohort of patient pseudarthrosis-derived primary cells. Results: We confirmed increased MAPK signaling in pseudarthrosis samples compared to patient-matched control samples. Pseudarthrosis samples were reproducibly associated with reduced expression of gene signatures implicated in osteoblast differentiation, skeletal development, and formation of the extracellular matrix. Expression of these gene signatures was significantly rescued following treatment with selumetinib, and to a lesser extent trametinib, concomitant with reduced MAPK signaling activation. Conclusions: Our study utilized patient-derived primary cells to demonstrate the molecular signatures associated with fracture pseudarthrosis and how this molecular dysregulation was reversed with MEK inhibitor treatment. Clinical relevance: MEK inhibitors may be repurposed to promote healing of fracture pseudarthroses in children with NF1.
2025-05-29 | GSE277653 | GEO
Project description:Cas9-expressing trametinib resistant MOLM-13 cell lines (TM1) were generated using the Cas9-Blst (Addgene, #52962) and expanded for genome-wide loss-of-function screens using the Y. Kosuke library (Addgene, #67989) Following transduction, cells cultured in the presence of trametinib (100 nM) or DMSO after lentiviral infection.
2024-02-22 | GSE235183 | GEO
Project description:Multi-omics characterization of MEK inhibitor resistant pancreatic cancer based on a genetically engineered mouse model-derived in vitro system
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Project description:Fourteen LGSOC cell lines were interrogated using whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics. Somatic mutation, copy-number aberrations, gene and protein expression were analyzed and integrated using different computational approaches. LGSOC cell line data was compared to publicly available LGSOC tumor data (AACR GENIE cohort), and also used for predictive biomarker identification of MEK inhibitor (MEKi) efficacy. Protein interaction databases were evaluated to identify novel therapeutic targets.
2021-05-17 | PXD019544 | Pride
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: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.
2022-07-06 | GSE206267 | GEO
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.
2022-07-06 | GSE206268 | GEO
Project description:BRAFV600E mutant melanomas treated with BRAF inhibitor (Dabrafenib) and MEK inhibitor (Trametinib) almost invariably develop drug resistance (DTR). Restored glycolysis, frequently found in clinical targeted therapy-resistant melanoma biopsies, has been shown to elicit drug resistance. How resumed glycolysis controls the emergence of acquired resistance, especially via intrinsic mechanisms that circumvent the BRAF/MEK module, remains unknown. Here, we identify lactylation of LSD1, induced by re-accumulated lactate in DTR melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with FosL1, thereby preventing its ubiquitination and degradation by E3 ligase tripartite-motif-containing protein 21 (TRIM21). In DTR melanoma cells, chromatin binding capacity of FosL1 was significantly strengthened due to reduced acetylation, which in turn increases selective chromatin enrichment of LSD1. We further demonstrate that lactylated LSD1 co-orchestrates gene transcription with FosL1 to repress ferroptosis in DTR cells via interfering with transferrin receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibitor (LSD1i) activates ferroptosis, resulting in drastic DTR melanoma regression in mice. Importantly, LSD1i-induced immunogenic ferroptosis synergizes with immune checkpoint blockade (ICB) in vivo. Together, our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in DTR melanoma, which provides a therapeutically actionable strategy to overcome acquired resistance to targeted therapy.
2025-02-13 | GSE256123 | GEO
Project description:BRAFV600E mutant melanomas treated with BRAF inhibitor (Dabrafenib) and MEK inhibitor (Trametinib) almost invariably develop drug resistance (DTR). Restored glycolysis, frequently found in clinical targeted therapy-resistant melanoma biopsies, has been shown to elicit drug resistance. How resumed glycolysis controls the emergence of acquired resistance, especially via intrinsic mechanisms that circumvent the BRAF/MEK module, remains unknown. Here, we identify lactylation of LSD1, induced by re-accumulated lactate in DTR melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with FosL1, thereby preventing its ubiquitination and degradation by E3 ligase tripartite-motif-containing protein 21 (TRIM21). In DTR melanoma cells, chromatin binding capacity of FosL1 was significantly strengthened due to reduced acetylation, which in turn increases selective chromatin enrichment of LSD1. We further demonstrate that lactylated LSD1 co-orchestrates gene transcription with FosL1 to repress ferroptosis in DTR cells via interfering with transferrin receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibitor (LSD1i) activates ferroptosis, resulting in drastic DTR melanoma regression in mice. Importantly, LSD1i-induced immunogenic ferroptosis synergizes with immune checkpoint blockade (ICB) in vivo. Together, our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in DTR melanoma, which provides a therapeutically actionable strategy to overcome acquired resistance to targeted therapy.
2025-02-13 | GSE256122 | GEO
Project description:Acute myeloid leukaemia (AML) continues to have a very high mortality and its treatment hasnot changed for more than 20 years.Here, we propose to apply genomic-wide screens to directly identify therapeutic vulnerabilitiesof AML using AML cells lines with pre-defined somatic mutations. Our studies will be basedon genome-wide CRISPR/CAs9 gRNA screens and will be used to identify drivers of drugresistance to standard chemotherapies.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
2015-02-03 | E-ERAD-335 | biostudies-arrayexpress