Browse
Submit Data
Databases
API
Help

Dataset Information

5 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics

ABSTRACT: Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T-cell lymphoma (CTCL) and multiple myeloma. The drugs lead to increasing acetylation levels of histones and other proteins, altered gene expression, and cell death. To characterize the mechanisms of action of these drugs in more detail, we systematically measured dose-dependent drug-induced changes in protein expression, acetylation, and phosphorylation in response to 21 clinical and pre-clinical KDACis. The resulting 872,000 dose-response curves revealed, for instance, poor selectivity of HDAC1, 2, 3, and 6 inhibitors in cells, strong cross-talk between acetylation and phosphorylation pathways, localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs), an underappreciated role of acetylation in protein structure and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be explored online in ProteomicsDB.

ORGANISM(S): Homo Sapiens

SUBMITTER: Miriam Abele

PROVIDER: PXD047419 | panorama | Sun Apr 21 00:00:00 BST 2024

REPOSITORIES: PanoramaPublic

ACCESS DATA

Json Xml

Similar Datasets

Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics

Project description:Lysine deacetylase inhibitors (KDACis) are approved for cutaneous T-cell lymphoma (CTCL) and multiple myeloma. Nevertheless, their mechanisms of action (MoA) remain elusive. To characterize the MoA of these drugs in more detail, we systematically measured dose-dependent changes in protein expression, acetylation, and phosphorylation in response to 21 clinical and pre-clinical KDACis. MV4-11 cells were treated for 6 h with vehicle control and 10 increasing doses of the respective drug (from 100 pM to 30 mM). PTM-carrying and unmodified peptides were analyzed separately by liquid chromatography tandem mass spectrometry (LC-MS/MS) for peptide and protein identification and quantification. Furthermore, time-dependent experiments were carried out for Vorinostat and Panobinostat at their respective pEC50 concentrations from the cell viability data. In an independent experiment, the subcellular proteomes of Panobinostat-treated cells were measured.

2023-12-08 | MSV000093608 | MassIVE

Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics

Project description:Kinase inhibitors (KIs) are important cancer drugs but often display polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same cells against 150 cancer drugs. The resulting 2,550 phenotypic drug profiles revealed distinct drug responses and the cellular activity landscapes derived from deep (phospho)proteomes (9-10,000 proteins and 10-27,000 phosphorylation sites per cell line) enabled several lines of analysis. For instance, connecting the (phospho)proteomic data with drug responses revealed known and novel mechanisms of action (MoAs) of kinase inhibitors and identified markers of drug sensitivity or resistance. All data is publically accessible via an interactive web application that enables exploration of this rich molecular resource for better understanding active signalling pathways in sarcoma cells, identifying treatment response predictors, and revealing novel MoA of clinical KIs.

2023-01-11 | MSV000091043 | MassIVE

Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics-2

2023-11-29 | MSV000093533 | MassIVE

Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics

Project description:Proteomics is making important contributions to drug discovery - from target deconvolution to mechanism of action (MoA) elucidation and the identification of biomarkers of drug response. Here, we introduce decryptE, a proteome-wide approach that measures the full dose-response characteristics of drug-induced protein expression changes which informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in >1 million dose-response curves that can be interactively explored online in ProteomicsDB and a custom-built ShinyApp. Analysis of the collective data provided molecular explanations for known phenotypic drug effects and uncovered novel aspects of the MoAs of human medicines. Most notable, HDAC inhibitors potently and strongly down-regulated the T-cell receptor complex resulting in impaired human T-cell activation in-vitro and ex-vivo. This not only offers a rational explanation for the efficacy of HDAC inhibitors in certain lymphomas and autoimmune diseases but also their poor performance in treating solid tumors.

2023-12-13 | MSV000093659 | MassIVE

Pharmacoproteomics identifies kinase pathways that drive the epithelial-mesenchymal transition and drug resistance in hepatocellular carcinoma

Project description:Hepatocellular carcinoma (HCC) is a complex and deadly disease lacking druggable genetic mutations. The limited efficacy of systemic treatments for advanced HCC implies that novel predictive biomarkers and drug targets are urgently needed. Most HCC drugs target protein kinases and their kinase-dependent signaling networks to drive HCC progression. To identify HCC signaling networks that determine responses to kinase inhibitors (KIs), we apply a pharmacoproteomics approach integrating kinome activity in 17 HCC cell lines with their responses to 299 KIs, resulting in a comprehensive dataset of pathway-based drug response signatures. By profiling patient HCC samples, we identify signatures of clinical HCC drug responses in individual tumors. Our analyses reveal kinase networks promoting the epithelial-mesenchymal transition (EMT) and drug resistance, including a FZD2-AXL-NUAK1/2 signaling module, whose inhibition reverses the EMT and sensitizes HCC cells to drugs. Our approach identifies cancer drug targets and molecular signatures of drug response for personalized oncology.

2018-12-15 | MSV000083236 | MassIVE

Chemical profiling of the genome with anti-cancer drugs defines target specificities

Project description:Many anti-cancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors can also evict histones. We performed a genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II inhibitors. We show that different drugs target different types of chromatin for induction of DNA damage and histone eviction. Topoisomerase inhibitors topotecan and etoposide similarly target transcriptionally active chromatin for DNA damage. Daunorubicin induces DNA breaks and evicts histones in active chromatin, thus quenching local DNA damage response. The analog aclarubicin evicts histones in H3K27me3-marked heterochromatin. These results can guide rational treatment decisions regarding these genome manipulating anti-cancer drugs. FAIRE-seq and g-H2AX ChIP-seq were performed on K562 cells after drug exposure

2015-05-10 | E-GEOD-60395 | biostudies-arrayexpress

Chemical and phosphoproteomics illuminate the cellular mode of action of AKT inhibitors

Project description:Due to its key role in dysregulated cellular signaling in cancer, AKT has been subject to intense drug discovery efforts leading to small molecule inhibitors investigated in clinical trials, notably breast cancer. To shed more light on how these drugs exert their therapeutic effects, we integrated chemoproteomic target affinity profiling using the kinobeads approach and phosphoproteomics for the five designated AKT inhibitors AZD5363, GSK2110183, GSK690693, Ipatasertib and MK-2206 in breast cancer cells. Kinobead analysis identified between four and 29 nanomolar targets for these compounds and revealed that AKT1 and AKT2 were the only common targets. Similarly, measuring the response of the phosphoproteome to the same inhibitors identified ~1,700 regulated phosphorylation sites among which 276 were regulated by all drugs. This analysis expanded the AKT signaling network by 119 phosphoproteins that may represent direct or indirect targets of AKT. Within this network, we found 41 regulated phosphorylation sites bearing the AKT substrate motif and recombinant kinase assays validated 16 as novel AKT substrates. These included CEP170 and FAM83H, which suggest a direct regulatory function of AKT in mitosis and cytoskeleton organization. In addition, a specific phosphorylation pattern on ULK1, FIP200, ATG13 and VAPB was found to represent an active state of ULK1, leading to elevated autophagy in response to AKT inhibition. And last, secretome analysis of AKT inhibitor-treated cells identified STC2 as a putative blood-based drug response marker that may be tested in patients in the future.

2022-01-21 | PXD015188 | panorama

Comprehensive evaluation of MEK inhibitors for malignant peripheral nerve sheath tumors reveals differences in efficacy and drug resistance development

Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas which lack effective drugs. Previous studies support the usefulness of MEK inhibitors (MEKis) for treating RAS-driven tumors, however, the lack of preclinical assessment of MEK inhibitors in MPNSTs limit the clinical application as well as the development of combination therapy. In this study, we comprehensively evaluated 8 MEK inhibitors in terms of efficiency, safety and mechanisms of resistance for treating MPNSTs. We identified the most promising MEK inhibitor, trametinib, for the treatment of MPNSTs. Through high-throughput transcriptomic sequencing and drug screening, we discovered the upregulation of integrin signaling contributing to MEK inhibitor resistance, termed as cell adhesion-mediated drug resistance (CAM-DR). We also confirmed MET overactivation in MEKi-resistant MPNST cells. These targets are potential solutions to overcome MEKi- resistance in clinical applications.

2022-07-26 | GSE174100 | GEO

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

Project description:Increased MITF expression contributes to melanoma progression and resistance to BRAF pathway inhibition. We show that, unexpectedly, lack of MITF is associated with more severe resistance to a range of inhibitors. Indeed, the presence of endogenous MITF was essential for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlated with expression of several activated receptor tyrosine kinases, most commonly AXL. The MITF-low/AXL-high/drug resistance phenotype was seen in roughly half of BRAF mutant and the majority of NRAS mutant melanoma cell lines. The dichotomous behavior of MITF in drug response was corroborated in vemurafenib-resistant biopsies, including MITF high and low clones in a relapsed patient. Drug cocktails containing AXL inhibitor enhanced melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. Experssion analysis by RNAseq of 14 melanoma cell lines.

2014-09-19 | E-GEOD-61544 | biostudies-arrayexpress

Drug sensitivity screening and genomic characterization of 45 HPV-negative head and neck carcinoma cell lines for novel biomarkers of drug efficacy [gene expression]

Project description:There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers, and point mutations in 45 human papillomavirus-negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK, and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to the EGFR inhibitor erlotinib was validated by gene silencing and from the data set at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series.

2018-07-06 | GSE108061 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data