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Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

ABSTRACT: PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (i.e., PARP1 catalytic inhibition vs. PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is incompletely understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib (1) results in highly efficient and specific PARP1 degradation. iRucaparib blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated PARylation signaling in intact cells. This strategy mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping. Finally, by depleting PARP1, iRucaparib protects muscle cells and primary cardiomyocytes from DNA damage-induced energy crisis and cell death. In summary, these compounds represent “non-trapping” PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Cervix Carcinoma

SUBMITTER: Shuai Wang

LAB HEAD: Yonghao Yu

PROVIDER: PXD014839 | Pride | 2019-08-01

REPOSITORIES: Pride

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Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

Project description:PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (i.e., PARP1 catalytic inhibition vs. PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is incompletely understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib (1) results in highly efficient and specific PARP1 degradation. iRucaparib blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated PARylation signaling in intact cells. This strategy mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping. Finally, by depleting PARP1, iRucaparib protects muscle cells and primary cardiomyocytes from DNA damage-induced energy crisis and cell death. In summary, these compounds represent “non-trapping” PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation.

2019-08-01 | PXD014836 | Pride

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

2019-08-01 | PXD014838 | Pride

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

2019-08-01 | PXD014840 | Pride

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

2019-08-01 | PXD014837 | Pride

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

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 | PXD029432 | Pride

Immunoprecipitated PARP1 interactome

Project description:Poly-(ADP-ribose) polymerase inhibitors (PARPi) elicit anti-tumour activity in homologous recombination defective cancers by promoting cytotoxic, chromatin-bound, “trapped” PARP1 DNA lesions. How cells process trapped PARP1 remains unclear. By exploiting wild-type or trapping-resistant PARP1 transgenes combined with rapid immunoprecipitation mass-spectrometry of endogenous proteins (RIME) and Apex2-proximity labelling, we generated proteomic profiles of trapped and non-trapped PARP1 complexes. This combined approach identified an interaction between PARP1 and the ubiquitin system including its central component - the ubiquitin-regulated p97 ATPase (aka VCP).

2021-10-05 | PXD024337 | Pride

PARP1-SNAI2 Transcription Axis Drives Resistance to PARP Inhibitor, Talazoparib (scRNA-Seq)

Project description:The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.

2022-07-07 | GSE202435 | GEO