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Genome-wide screening reveals the key genes that are responsible for trametinib-induced apoptosis

ABSTRACT: Genome-wide screening reveals the key genes that are responsible for trametinib-induced apoptosis

PROVIDER: PRJNA640634 | ENA |

REPOSITORIES: ENA

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Genome-wide screening reveals the key genes that are responsible for trametinib-induced apoptosis

Project description:To explore the geness that are responsible for trametinib-induced apoptosis, we performed Genome-scale CRISPR-Cas9 knockout screening in GSU with 0.015% DMSO or 15 nM trametinib for 14 days. We found that TP53 is critical for executing trametinib-induced apoptosis.

2023-06-19 | GSE152846 | GEO

Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD-1/PD-L1 axis blockade via Id1 downregulation

Project description:The identification of novel therapeutic strategies to overcome the intrinsic or acquired resistance to trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a major challenge. This study analyzes the effects of trametinib in Id1, a key factor involved in the oncogenic KRAS pathway, and investigates the Id1 role in acquire resistance and synergy with immunotherapy in KRAS-driven LUAD. Restoring the antitumor immune response by blocking programmed-cell death protein 1 (PD-1) and programmed-cell death-ligand 1 (PD-L1) pathway represents a major breakthrough in non-small-cell lung cancer (NSCLC) treatment. Nevertheless, a high proportion of LUAD patients with KRAS alterations remain refractory to this therapy. Material and Methods: To explore whether MEK1/2 inhibition reduces Id1 expression, in vitro and in vivo experiments were conducted in KRAS-mutant NSCLC cells and murine models. RNAseq analysis was performed to elucidate the pathways involved in Id1 inhibition. Apoptosis and PD-L1 expression was measured by flow cytometry. Synergy of trametinib combined with anti-PD1 was investigated in KRAS-mutant LUAD mouse models. Results: Using preclinical syngeneic KRAS-mutant lung cancer mouse models, we demonstrate that trametinib synergizes with PD-1 blockade to reduce lung cancer progression and increase mice overall survival. This antitumor activity was linked to the degradation of Id1 via proteasome, and an enhanced INF-Y-mediated PD-L1 tumor cell expression in KRAS-mutant tumor cells. This effect required CD8+ T cells, boosted the intratumoral CD8+/Treg ratio, reducing the intratumoral Treg/CD4+ ratio. Conclusions: Our data may support the role of Id1 in the trametinib antitumoral effect, sustaining the mitogen-activated protein kinases (MAPK) signaling pathway involved in the trametinib acquired resistance cells and sensitizing KRAS-mutant lung tumors to PD-1 inhibitors, through PD-L1 overexpression.

2024-05-17 | GSE236258 | GEO

Whole-exome sequencing of genomic DNA extracted from patient-derived melanoma cell lines resistant to vemurafenib (PLX) or trametinib (TRA)

Project description:Whole-exome sequencing was performed on DNA samples extracted from seven melanoma cell lines resistant to either vemurafenib (BRAF V600E inhibitor) or trametinib (MEK1/2 inhibitor). The aim of the experiment was to search for genetic alterations responsible for phenotypic diversity of melanoma cell lines reported at the level of cell morphology, activity of signaling pathways essential for melanoma development and progression, and resistance to targeted therapeutics.

2018-10-20 | E-MTAB-7248 | biostudies-arrayexpress

Whole-exome sequencing of genomic DNA from patient-derived melanoma cell lines resistant to either vemurafenib (PLX) or trametinib (TRA).

2019-06-15 | E-MTAB-7991 | biostudies-arrayexpress

Differentially expressed genes in iKRAS cell treated with Trametinib, 2DG and Combo

Project description:To identify the differentially expressed gene in ikras cells treated with Trametinib, 2DG and Trametinib/2DG combination. Two ikras cells were used for transcriptomics analysis by RNAseq.

2021-06-07 | GSE176242 | GEO

Response and resistance of low grade ovarian cancer cells to trametinib

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.

2020-04-15 | GSE148648 | GEO

Transcriptomic analysis of T84 colon carcinoma cell line treated with trametinib, JQ1 or their combination

Project description:T84 cells were treated with DMSO, 30nM trametinib (MEKi), 1µM JQ1 (BRD4i) or the combination of trametinib and JQ1 (combo) for 24h.

2018-10-23 | GSE118548 | GEO

Transcriptomic profile of trametinib on LPS-mediated gene expression in murine peritoneal macrophages

Project description:To determine the underlying mechanisms by which trametinib affected LPS-induced inflammatory response in macrophages, we performed microarrays to define the global gene expression in murine peritoneal macrophages treating with trametinib or vehicle followed by LPS stimulation.

2021-07-12 | GSE134486 | GEO

Identification and Characterization of Key Genes Responsible for Weedy and Cultivar Growth Types in Soybean

Project description:Identification and Characterization of Key Genes Responsible for Weedy and Cultivar Growth Types in Soybean

| PRJNA779255 | ENA

Transcriptomic analysis of trametinib-resistant HCT116 colorectal carcinoma cells compared to the parental control cells

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.

2018-10-23 | GSE118490 | GEO

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