Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1170198 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The delicate balance of protein phosphorylation is often disrupted in cancers, with hyperactivity of kinases and inactivation of phosphatases driving cell proliferation and survival pathways. PTPRH, a receptor-like protein tyrosine, is deregulated or mutated in certain cancers, including non-small cell lung cancer (NSCLC). Nonetheless, the biological processes that PTPRH is involved in and how it may contribute to tumorigenesis are unknown. We aimed to understand how ovexpression of PTPRH affects tyrosine kinase signaling and in which biological processess this tyrosine phosphatase is involved in. We observed that overexpression of the phosphatase downregulates multiple oncogenic signature pathways and modulates the gene expression of 34 protein tyrosine phosphatases and 45 tyrosine kinases, EGFR included. Moreover, we report for the first time that PTPRH is primarily involved in translation and RNA-associated pathways. Together, these results shed light on the importance of PTPRH in regulating biological and cellular processes and how its inactivation may support cancer progression.
2024-06-18 | GSE270167 | GEO
Project description:Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy, characterized by expansion of immature leukemic blasts in the bone marrow. In AML, specific tyrosine kinases have been implicated in leukemogenesis, and are associated with poor treatment outcome. However, targeted therapy using kinase inhibitors (KIs) has had limited success, and may be improved by proper patient selection. We performed phosphotyrosine (pY) based, label-free phosphoproteomics to identify hyperphosphorylated, active kinases in two FLT3+ AML Pt samples.
2020-03-02 | PXD015639 | Pride
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:Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy, characterized by expansion of immature leukemic blasts in the bone marrow. In AML, specific tyrosine kinases have been implicated in leukemogenesis, and are associated with poor treatment outcome. However, targeted therapy using kinase inhibitors (KIs) has had limited success, and may be improved by proper patient selection. We performed phosphotyrosine (pY) based, label-free phosphoproteomics to identify hyperphosphorylated, active kinases in two FLT3+ AML Pt samples and this data is deposited in PXD015639 . Here are the corresponding lysate samples
2020-03-02 | PXD015662 | Pride
Project description:Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes (MDS). Although anomalies of tyrosine-kinases or proteins involved in cytokine signaling are common in MPN, the pathophysiology of atypical MPN is still elusive. Since deregulation of microRNAs has been involved in the biology of various cancers, we screened the miRNome of aMPN compared to CML or reactive hyperleukocytosis (RHL) states. The study highligths the overexpression of miR-10a in the aMPN group
2017-12-01 | GSE75666 | GEO
Project description:The transcription factors STAT5A and STAT5B are essential downstream mediators of many tyrosine kinases, particularly in hematopoietic cancers. As such, STAT5 is activated by FLT3-ITD, which is a constitutively active tyrosine kinase driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 function is of significant clinical value. Here, we describe the novel small molecular weight inhibitor AC-4-130 that directly binds to the phosphotyrosine (pY)-binding pocket of the STAT5 SH2 domain, thereby disrupting STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent induction of gene transcription. AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Importantly, AC-4-130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. In summary, we report the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor that can efficiently block pathological levels of STAT5 activity in AML. The synergistic effects of AC-4-130 tyrosine kinase inhibitors as well as emerging treatment strategies provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.
2018-09-03 | GSE103510 | GEO
Project description:Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy, characterized by expansion of immature leukemic blasts in the bone marrow. In AML, specific tyrosine kinases have been implicated in leukemogenesis, and are associated with poor treatment outcome. However, targeted therapy using kinase inhibitors (KIs) has had limited success, and may be improved by proper patient selection. We performed phosphotyrosine (pY) based, label-free phosphoproteomics to identify hyperphosphorylated, active kinases in AML cell lines as targets and predictive biomarkers to select KIs for treatment. We identified 3605 class I phosphorylation sites in 16 AML cell lines (EOL-1, KG-1a, MM6, KG-1, ME-1, NB-4, Kasumi-3, MV4-11, THP-1, HEL, HL-60, Kasumi-1, Kasumi-6, ML-2, OCI-AML3, MOLM-13) that exhibited large variation in the number and level of phosphopeptides per cell line (241-2764). Ranking analyses successfully pinpointed the hyperactive kinases PDGFRA, FGFR1, KIT, and FLT3 in eight cell lines with a corresponding kinase mutation. Additionally, we identified unexpected drivers in two more cell lines (PDGFRA in Kasumi-3 and FLT3 in MM6) which proved sensitive to specific kinase inhibitors. Six cell lines without a clear receptor tyrosine kinase (RTK) driver showed evidence of MAPK1/3 activation, consistent with the presence of activating RAS mutations. Our data show the potential of pY phosphoproteomics to identify key drivers in AML cells, and the predictive value of the phosphoproteome profiles in TKi selection for targeted treatment.
2019-11-11 | PXD007237 | Pride
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
2008-12-05 | GSE13808 | GEO
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:The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases (RTKs), as it is required for full RAS-ERK activation to promote cell proliferation and survival programs. SHP2 allosteric inhibitors act by stabilizing SHP2 in its auto-inhibited conformation and they are currently being tested in clinical trials for tumors with over-activation of the RAS/ERK pathway, alone and in various drug combinations. Using in vitro models, we established acquired resistant cell lines to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD-positive AML cell lines. We performed both label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics to reveal that AML cells can restore phosphorylated ERK (pERK) in presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induces the tyrosine phosphorylation and feedback-activation of the FLT3 receptor, which in turn phosphorylates SHP2 on Tyrosine 62. This phosphorylation stabilizes SHP2 in its open conformation, preventing SHP099 binding, thus resulting in resistance. Combinatorial inhibition of SHP2 and MEK or SHP2 and FLT3 prevents pERK rebound and resistant cell growth. We observed the same mechanism in a FLT3-mutated B-ALL cell line and in the inv(16)/KITD816Y AML mouse model. Finally, we show that allosteric SHP2 inhibition does not impair the clonogenic ability of normal bone marrow progenitors, supporting its future use for clinical applications.
2023-03-10 | PXD030338 | Pride