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Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [scRNA-seq]

ABSTRACT: Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [scRNA-seq]

PROVIDER: PRJNA1229603 | ENA |

REPOSITORIES: ENA

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Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer

Project description:Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer

| PRJNA1230186 | ENA

Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [scTCR-Seq]

Project description:Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [scTCR-Seq]

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Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [RNA-seq]

Project description:Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [RNA-seq]

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Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [exome-Seq]

Project description:Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [exome-Seq]

| PRJNA1230751 | ENA

Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [exome-Seq]

Project description:Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). HRD also activates the cyclic GMP–AMP synthase (cGAS)-STimulator of INterferon Genes (STING)-Interferon (IFN) pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of thirty-five breast cancer (BC) patient-derived xenografts (PDX) and mouse-derived allografts (MDA). PARPi sensitivity correlated with HRD, increased genomic instability, and activation of the cGAS-STING-IFN signaling pathway. Single-cell analyses showed that IFN signaling and IFN-based immune interactions were suppressed in preclinical models with acquired resistance to PARPi, lacking concomitant clonal expansion of functional CD8+ T cells. However, the combination of PARPi and a novel STING agonist (STINGa) increased immune infiltration and resulted in superior antitumor activity in these tumors. Notably, the efficacy of PARPi monotherapy and the combination treatment with a STINGa was dependent on Natural Killer (NK) cells. In agreement, BC patients with BRCA1/BRCA2 mutations and good responses to PARPi showed higher abundancy of CD56+ NK cells in the tumor microenvironment and treatment-engaged CD56bright NK cells in the peripheral immune compartment, compared to those with poor responses. Therefore, these findings propose the combination of PARPi and STINGa as a potential novel strategy to enhance the therapeutic response in patients with acquired PARPi resistance and highlight a pivotal role of NK cells in the PARPi antitumor activity.

2025-03-03 | GSE290913 | GEO

Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [scTCR-Seq]

2025-03-03 | GSE290912 | GEO

Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [RNA-seq]

2025-03-03 | GSE290828 | GEO

Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer [scRNA-seq]

2025-03-03 | GSE290706 | GEO

Lack of synergy between AR targeted therapies and PARP inhibition in homologous recombination- proficient prostate cancer

Project description:Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous-recombination proficient prostate cancer.

2026-01-13 | GSE315878 | GEO

Harnessing STING Signaling and Natural Killer Cells to overcome PARP Inhibitor Resistance in Homologous Recombination Repair altered Breast Cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-03-03 | GSE290830 | GEO