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Phospho proteomic profiling of Olaparib in UWB1.289 cells

ABSTRACT: Explore phosphorylation changes in UWB1.289 cells upon treatment with Olaparib

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Uwb1.289 Cell, Cell Line Cell

SUBMITTER: Maria Faelth Savitski

LAB HEAD: Marcus Bantscheff

PROVIDER: PXD046613 | Pride | 2024-05-13

REPOSITORIES: Pride

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			Action	DRS
	03126_F1_R1_P0253186C01_TMT10.raw.gz	Raw
	03126_F1_R1_P0253186C02_TMT10.raw.gz	Raw
	03126_F1_R1_P0253186C03_TMT10.raw.gz	Raw
	03126_F1_R1_P0253186C04_TMT10.raw.gz	Raw
	03126_F1_R1_P0253186C05_TMT10.raw.gz	Raw

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Publications

Network integration of thermal proteome profiling with multi-omics data decodes PARP inhibition.

Burtscher Mira L ML Gade Stephan S Garrido-Rodriguez Martin M Rutkowska Anna A Werner Thilo T Eberl H Christian HC Petretich Massimo M Knopf Natascha N Zirngibl Katharina K Grandi Paola P Bergamini Giovanna G Bantscheff Marcus M Fälth-Savitski Maria M Saez-Rodriguez Julio J

Molecular systems biology 20240307 4

Complex disease phenotypes often span multiple molecular processes. Functional characterization of these processes can shed light on disease mechanisms and drug effects. Thermal Proteome Profiling (TPP) is a mass-spectrometry (MS) based technique assessing changes in thermal protein stability that can serve as proxies of functional protein changes. These unique insights of TPP can complement those obtained by other omics technologies. Here, we show how TPP can be integrated with phosphoproteomic ...[more]

PMID: 38454145

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Expression proteomic profiling of Olaparib in UWB1.289 cells

Project description:Explore protein abundance changes in UWB1.289 cells upon treatment with Olaparib

2024-05-13 | PXD046536 | Pride

Off-target profiling of Olaparib using Thermal Proteome Profiling

Project description:Explore off-targets of Olaparib using 2D Thermal Proteome Profiling (2D-TPP)

2024-05-13 | PXD046614 | Pride

Identification of different gene expression levels in gastric cancer cell lines with drug treatment

Project description:A microarray time series was generated to identify which factor is expressed at different levels in two different gastric cancer cell lines, SNU 601 and SNU 668. These cell lines were treated for three different periods of time (24h, 48h, and 72h) with 1umol/L of olaparib or DMSO. Total RNA was extracted by using TRI reagent in accordance with the manufacturer`s instructions, and hybridized to an affymetrix GeneChip Human Gene 1.0 ST array. The results were normalized to the RObust Multi-Array Avarage (RMA) and analyzed.

2012-03-02 | E-MTAB-1012 | biostudies-arrayexpress

RNA-Seq of PARPi-resistant ovarian cancer cells

Project description:We have previously established an in vitro model of PARPi-resistant ovarian cancer by long-term exposure of UWB1.289 ovarian cancer cells (and their isogenic derivatives UWB1.289+BRCA1) to incrementally ascending olaparib concentrations. After finalizing this model, we performed RNA-seq, in order to identify differentially expressed transcript in the PARPi-resistant cells, with a focus on genes related to DNA-repair, multi-drug resistance and EMT. As a result, we show that the phenotype of PARPi resistance is associated with EMT-like traits and up-regulation of selective multi-drug related transcripts.

2023-07-31 | GSE235980 | GEO

Integrative functional proteomics identifies PARP1 protein complex differences and PARP inhibitor-mediated DDR and AKT-mTOR signaling in ovarian carcinoma: ADP-Ribosylation

Project description:BRCA1/2-deficient ovarian carcinoma (OC) has been shown to be particularly sensitive to PARP inhibitors (PARPis) and BRCA1/2 mutation status is currently used as a predictive biomarker for PARPi therapy. Despite eliciting major clinical benefit for the majority of patients, a significant proportion of BRCA1/2-deficient OC tumors do not respond to PARPis for reasons that are incompletely understood. Using an integrated chemical, phospho- and ADP-ribosylation proteomics approach we sought to develop additional mechanism-based biomarker candidates for PARPi therapy in OC and identify new targets for combination therapy to overcome primary resistance. Chemical proteomics with PARPi baits in a BRCA1-isogenic OC cell line pair, as well as patient-derived BRCA1-profiecient and deficient tumor samples, and subsequent validation by co-immunoprecipitation showed differential PARP1 and PARP2 protein complex composition with Ku70 and Ku80 in PARPi-sensitive, BRCA1-deficient UWB1.289 (UWB) cells compared to PARPi-insensitive, BRCA1-reconstituted UWB1.289 (UWB+B) cells. Global phosphoproteomics and ADP-ribosylation proteomics furthermore revealed that rucaparib induced the cell cycle pathway and NHEJ pathway in UWB cells, but down-regulated ErbB signaling in UWB+B cells. In addition, we observed AKT PARylation and pro-survival AKT-mTOR signaling in UWB+B cells after PARPi treatment. Consistently, synergy of PARPis with DNAPK or AKT inhibitors was more pronounced in UWB+B cells identifying these pathways as actionable vulnerabilities. In conclusion, the combination of chemical proteomics, phosphoproteomics and ADP-ribosylation proteomics can identify differential PARP1/2 complexes and diverse, but actionable drug compensatory signaling in OC.

2022-10-21 | PXD029428 | Pride

Olaparib based photo-affinity probes for PARP-1 detection in living cells

Project description:The poly-ADP-ribose polymerase (PARP) is a protein from the family of ADP-ribosyltransferases that catalyzes poly adenosine diphosphate ribose (ADPR) formation in order to attract the DNA repair machinery to DNA damage sites. Inhibition of PARP activity by olaparib can cause cell death which is of clinical relevance in some tumor types. This demonstrates that quantification of PARP activity in the context of living cells is of great importance. In this work we present the design, synthesis and biological evaluation of photo-activatable affinity probes inspired by the olaparib molecule which are equipped with a diazirine for covalent attachment upon activation by UV light and a ligation handle for the addition of a reporter group of choice. SDS-PAGE, western blotting and label-free LC-MS/MS quantification analysis show that the probes target the PARP-1 protein and are selectively outcompeted by olaparib suggesting binding in the same enzymatic pocket.

2020-04-29 | PXD018661 | Pride

Integrative functional proteomics identifies PARP1 protein complex differences and PARP inhibitor-mediated DDR and AKT-mTOR signaling in ovarian carcinoma: Chemical Proteomics

Project description:BRCA1/2-deficient ovarian carcinoma (OC) has been shown to be particularly sensitive to PARP inhibitors (PARPis) and BRCA1/2 mutation status is currently used as a predictive biomarker for PARPi therapy. Despite eliciting major clinical benefit for the majority of patients, a significant proportion of BRCA1/2-deficient OC tumors do not respond to PARPis for reasons that are incompletely understood. Using an integrated chemical, phospho- and ADP-ribosylation proteomics approach, we sought to develop additional mechanism-based biomarker candidates for PARPi therapy in OC and identify new targets for combination therapy to overcome primary resistance. Chemical proteomics with PARPi baits in a BRCA1-isogenic OC cell line pair, as well as patient-derived BRCA1-profiecient and deficient tumor samples, and subsequent validation by co-immunoprecipitation showed differential PARP1 and PARP2 protein complex composition with Ku70 and Ku80 in PARPi-sensitive, BRCA1-deficient UWB1.289 (UWB) cells compared to PARPi-insensitive, BRCA1-reconstituted UWB1.289 (UWB+B) cells. Global phosphoproteomics and ADP-ribosylation proteomics furthermore revealed that rucaparib induced the cell cycle pathway and NHEJ pathway in UWB cells, but down-regulated ErbB signaling in UWB+B cells. In addition, we observed AKT PARylation and pro-survival AKT-mTOR signaling in UWB+B cells after PARPi treatment. Consistently, synergy of PARPis with DNAPK or AKT inhibitors was more pronounced in UWB+B cells identifying these pathways as actionable vulnerabilities. In conclusion, the combination of chemical proteomics, phosphoproteomics and ADP-ribosylation proteomics can identify differential PARP1/2 complexes and diverse, but actionable drug compensatory signaling in OC.

2022-10-21 | PXD029424 | Pride

The non-canonical PARP1 inhibitor target, PARP16, contributes to talazoparib polypharmacology and synergy with WEE1 inhibitors: Chemical Proteomics Cal51

Project description:PARP1 inhibitors (PARP1is) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determined the differential efficacy of multiple clinical PARP1is in SCLC cells. Compared to the other PARP1is (rucaparib, olaparib and niraparib), talazoparib displayed the highest potency across SCLC, also in SLFN11-negative cells. Chemical proteomics identified PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduced cell survival, particularly in combination with PARP1 inhibition. Drug combination screening revealed talazoparib synergy with the WEE1/PLK1 inhibitor, adavosertib. Global phosphoproteomics identified disparate effects on cell cycle and DNA damage response signaling, illustrating underlying mechanisms. Synergy with adavosertib was more pronounced for talazoparib than olaparib and silencing PARP16 further reduced cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib’s overall mechanism of action and constitutes a new actionable target in SCLC.

2021-07-21 | PXD020520 | Pride

Response Profiling Using Shotgun Proteomics Enables Establishing Global Metallodrug Mechanisms of Action - cytoplasmic proteins of KP46-treated HCT 116 epithelial cells

Project description:Response profiling using shotgun proteomics for establishing global metallodrug mechanisms of action in two colon carcinoma cell lines, HCT116 and SW480, was applied and evaluated with the clinically approved arsenic trioxide. Surprisingly, the complete established mechanism of action of arsenic trioxide was observed by protein regulations in SW480, but not in HCT116 cells. Comparing the basal protein expression in the two cell lines revealed an 80% convergence of protein identifications, but with significant expression differences, which in turn seem affect the extent of protein regulation. For example, while a clear-cut redox response was observed in SW480 cells upon arsenic treatment, such an effect was lacking in HCT116 cells and the latter express drastically higher levels of the involved redox proteins. Response profiling was then used to investigate four anticancer metallodrugs (KP46, KP772, KP1339 and KP1537) by means of functional groups of proteins and mapped their effects according to DNA repair, endocytosis, protection from oxidative stress, protection from endoplasmatic reticulum (ER) stress, cell adhesion and mitochondrial function. We were able to characterize the global effects of these metallodrugs on the proteome and generate hypotheses on hitherto unrecognized mechanisms. Significant differences in the two colon cell lines strongly suggest that knowledge of mechanistic hallmarks of anticancer metallodrug action are imperative for the design of clinical studies and that outcome may be enhanced by means of patient stratification strategies according to these hallmarks.

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The non-canonical PARP1 inhibitor target, PARP16, contributes to talazoparib polypharmacology and synergy with WEE1 inhibitors: Chemical Proteomics

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