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Project description:CRISRP screens reveal determinants of PARP inhibitor response in prostate cancer
| PRJNA781904 | ENA
Project description:Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer.
| S-EPMC9845315 | biostudies-literature
Project description:Analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells. The hypothesis tested in the present study was that enzalutamide influences the expression of genes that are involved in important bioprocesses in prostate cance rcells, including DNA damage response genes and this effect may synergize with poly(ADP-ribose) polymerase inhibitor olaparib in cytotoxicity to prstate cancer cells. prostate cancer cells were pretreated with enzalutamide or vehicle control DMSO for 24 h, followed by treatment with enzalutamide, olaparib, enzalutamide+olaparib, or vehicle control DMSO for 48 h. Gene expression in enzalutamide+olaparib-treated cells was compared with taht in vehicle control- and single agent-treated cells.
2016-07-03 | E-GEOD-69249 | biostudies-arrayexpress
Project description:Acquisition of resistance to the PARP inhibitor, Olaparib, constitutes a major challenge for the treatment of advanced prostate cancer. The purpose of this study was to identify molecular targets responsible for the development of acquired Olaparib resistance in advanced prostate cancer. Towards this goal, next-generation sequencing (NGS)-based gene expression profiling (RNA-Sequencing; RNA-Seq) was performed on castration-sensitive prostate cancer (CSPC)/Olaparib-sensitive LNCaP cells, castration-sensitive prostate cancer (CSPC)/Olaparib-resistant LN-OlapR cells, castration-resistant prostate cancer (CSPC)/Olaparib-sensitive C4-2B cells, and castration-resistant prostate cancer (CSPC)/Olaparib-resistant 2B-OlapR cells.
2023-12-06 | GSE249514 | GEO
Project description:Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations. Methods: We examined if olaparib, when combined with IgG1 antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab. Results: NK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15RA further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2, and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma. Conclusions: These studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.
2018-12-11 | GSE121682 | GEO
Project description:In this study, a population of knockout cells was generated using the GeCKO v2 sgRNA library. The population of knockout cells was treated with the PARP inhibitor olaparib for 14 days. Over this time, knockout cells that were sensitive to olaparib treatment would die and a population of knockout cells that was resistant to olaparib treatment remained. Cells from olaparib and DMSO conditions and the sgRNA cassette in the knockout cells was amplified and sequenced to identify synthetic lethal or suppressor interactions with olaparib treatment.
2020-08-01 | GSE145743 | GEO
Project description:PARP inhibitors have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) patients with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARP inhibitors, such as Olaparib. Here, we present compelling evidence that PARP inhibitor sensitivity is associated with cell cycle dysfunction, independent of homologous recombination deficiency (HRD) /BRCA status. Through high-throughput drug screening with a cell cycle kinase inhibitor library, we identified XL413, a potent CDC7 inhibitor, which can synergistically enhance the anti-cancer efficacy of Olaparib. Mechanistically, we demonstrate that the combined administration of XL413 and Olaparib induced considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type-I interferon response was triggered through the induction of the cGAS/STING signaling pathway. Using a murine syngeneic tumor model, we further demonstrate that the combination treatment enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents a novel treatment strategy for patients with advanced OV by combining CDC7 and PARP inhibitiors, offering a promising therapeutic approach forpatients whith limited response to PARP inhibitors.
2024-12-18 | GSE247622 | GEO
Project description:Analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells. The hypothesis tested in the present study was that enzalutamide influences the expression of genes that are involved in important bioprocesses in prostate cance rcells, including DNA damage response genes and this effect may synergize with poly(ADP-ribose) polymerase inhibitor olaparib in cytotoxicity to prstate cancer cells.
2016-01-01 | GSE69249 | GEO
Project description:PARP inhibitor olaparib induces the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, human high-grade serous ovarian cancer (HGSC)–derived organoids, and HGSC patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication of cancer cells after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, could escape senescence via restitutional multipolar endomitosis and other modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell production. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance.
2023-08-08 | GSE229119 | GEO
Project description:Polyadenosine-diphosphate-ribose polymerase (PARP) inhibitors cause deoxyribonucleic acid (DNA) damage that can be lethal to cells with deficient repair mechanisms. A number of PARP inhibitors are being tested as treatments for men with prostate cancer, both as monotherapies and in combinations that are based on purported synergies in treatment effect. While the initial single-agent development focused on men with identified deficiencies in DNA-repair pathways, broader patient populations are being considered for combination approaches. This review summarizes the current clinical development of PARP inhibitors and explores the rationale for novel combination strategies.
| S-EPMC7081465 | biostudies-literature