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CRISRP screens reveal determinants of PARP inhibitor response in prostate cancer

ABSTRACT: Gene expression profilings for prostate cancer cells after olaparib treatment

ORGANISM(S): Homo sapiens

PROVIDER: GSE189186 | GEO | 2022/03/31

REPOSITORIES: GEO

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CRISRP screens reveal determinants of PARP inhibitor response in prostate cancer

Project description:CRISRP screens reveal determinants of PARP inhibitor response in prostate cancer

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CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.

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.

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Genome-wide analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells

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

Transcriptome profiling of Olaparib-resistant (OlapR) prostate cancer cell lines

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.

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Immunotherapy Utilizing NK cells and ADCC Mediating Agents with Poly (ADP-ribose) polymerase (PARP) Inhibition

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.

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Genome-wide CRISPR knockout screen using GeCKO v2 to identify synthetic lethal interactions with the PARP inhibitor Olaparib

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Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

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

PARP inhibitor combinations in prostate cancer.

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Next Generation Sequencing of the transcriptomes of prostate cancer cells with or without ectopic expression of miR-5100

Project description:Gene expression profilings for prostate cancer cells after miR-5100 overexpression

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