Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA311917 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Expression data from MDA-MB231 human breast cancer cells treated with metalloproteinase inhibitor (10uM BB94), MEK inhibitor (3uM PD325901), or DMSO control shows substantial overlap in the transcriptional responses arising from MEK and protease inhibition, suggesting a shared mechanism of action. Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTKs) including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of melanoma patients treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured non-invasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.
2016-03-21 | GSE77868 | GEO
Project description:Tyrosine kinase activity profiling of metatstatic malignant melanoma and normal skin tissue samples was performed using peptide kinase arrays. All samples were run in triplicates with and withouth inhbitor PLX4032 and Sutent Malate in order to identify how tyrosine kinases responds to kinase inhibitor treatment, ex vivo.
2013-01-17 | E-MTAB-1245 | biostudies-arrayexpress
Project description:DS-6051b is an orally administered inhibitor of the tyrosine kinases (ROS1) and neurotropic tyrosine kinase receptors (NTRK). This phase 1 first-in-human study evaluates safety and tolerability of DS-6051b in cancer subjects and identify a recommended phase 2 dose (RP2D). In addition, this study will also assess the pharmacokinetic (PK)/pharmacodynamic (PD) profiles and preliminary efficacy of DS-6051b.
| 2177400 | ecrin-mdr-crc
Project description:CD8+ T cell immune responses are regulated by multi-layer networks, while the post-translational regulations remain largely unknown. Transmembrane ectodomain shedding is an important post-translational process regulating receptor expression and signal transduction by proteolytic cleavage of membrane proteins. Here, by targeting sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by ectodomain shedding in CD8+ T cells. Transcriptomic and proteomic analysis revealed the involvement of post-transcriptional/translational regulations in CD8+ T cells. T cell-specific deletion of ADAM17 led to a dramatic increase of effector CD8+ T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8+ T cells by cleavage of membrane CD122. ADAM17 deficient CD8+ T cells had elevated CD122 expression and response to cytokines IL-2 and IL-15. Intriguingly, inhibition of ADAM17 in CD8+ T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumor. Our findings reveal a critical post-translational regulation in CD8+ T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity. We then performed gene expression profiling analysis using data obtained from RNA-seq of 10 samples from two groups.
2024-07-20 | GSE236582 | GEO
Project description:Tyrosine Kinase Inhibitor Cardiotoxicity
| PRJNA352077 | ENA
Project description:Here we describe a bead-based method capable of profiling tyrosine kinase phosphorylations in a multiplexed, high-throughput and low-cost manner. This approach allows for the discovery of tyrosine kinase-activating events, even when the DNA sequence is wild-type. In an effort to pilot the establishment of a tyrosine kinase activation catalog, we profiled tyrosine phosphorylation levels of 62 tyrosine kinases in 130 human cancer lines, and followed-up on the frequent SRC phosphorylation in glioblastoma. Keywords: quantitative measurements of tyrosine phosphorylation levels on tyrosine kinases Total protein lysates were collected from 130 cancer cell lines. Tyrosine phosphorylation levels on 62 tyrosine kinases were measured with the bead assay.
2010-06-24 | E-GEOD-13808 | biostudies-arrayexpress
Project description:The catalytic activity of Abl family kinases is tightly regulated in cells by a complex set of intra- and intermolecular interactions and post-translational modifications. Abl family kinases are activated by diverse cellular stimuli, one of them being receptor tyrosine kinase signaling. For example, platelet-derived growth factor receptor beta (PDGFRβ) has been identified as a potent activator of Abl family kinases. However, the molecular mechanism by which PDGFRβ engages and activates Abl family kinases is not known. We report here the molecular mechanism by which PDGFRβ interacts, phosphorylates and activates Abl2 kinase. We found that PDGFRβ binds and phosphorylates Abl2 both in vitro and in cells. We also identified several novel PDGFRβ phosphorylation sites on Abl2, including Y116, Y139 and Y161 on the SH3 domain, and Y299, Y303 and Y310 on the kinase domain. Of notable interest, Y116, Y161, Y272 and Y310 are all located near the SH3/SH2-kinase linker interface, which help maintain Abl family kinases in an auto-inhibited conformation. Mutation of these four tyrosine (Y116, Y161, Y272 and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2 kinase activity. These findings provide a mechanism to understand how receptor tyrosine kinases activate Abl family kinases, and how Abl kinases are precisely regulated through different phosphorylation events.
2022-02-17 | PXD025896 | Pride
Project description:Protein tyrosine kinases are involved in regulating growth and proliferation in cells and are often hyperactive in cancerous tissue. Tyrosine kinase inhibitors have been used to limit hyperactivity but become ineffective due to the appearance of resistance mutations. A common trait of hyperactive protein kinases is its strict client relationship with molecular chaperone Hsp90. However, the mechanism behind Hsp90 client kinase recognition is poorly understood. Here we measure the functional effect of thousands of single amino acid variants in the Src kinase domain to identify positions invovled in Hsp90 client recognition.
2023-05-22 | GSE218190 | GEO
Project description:Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT or PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, producing high expression levels of the oncogene required for tumor growth. Though kinase inhibition is an effective therapy for many GIST patients, disease progression from kinase resistance mutations is common, and no other efficacious classes of systemic therapy exist. Given GIST’s reliance upon enhancer-driven expression of an RTK, we hypothesized that the enhancer domain could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell cycle arrest, apoptosis and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to synergistic cytotoxic effects in vitro and in vivo, with BBIs preventing tumor growth in TKI-resistant xenografts. A novel mechanism of resistance to select BBIs was found in GIST attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST.
2019-01-23 | GSE113215 | GEO
Project description:Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT or PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, producing high expression levels of the oncogene required for tumor growth. Though kinase inhibition is an effective therapy for many GIST patients, disease progression from kinase resistance mutations is common, and no other efficacious classes of systemic therapy exist. Given GIST’s reliance upon enhancer-driven expression of an RTK, we hypothesized that the enhancer domain could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell cycle arrest, apoptosis and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to synergistic cytotoxic effects in vitro and in vivo, with BBIs preventing tumor growth in TKI-resistant xenografts. A novel mechanism of resistance to select BBIs was found in GIST attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST.
2019-01-23 | GSE113207 | GEO