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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE290830 | GEO | 2025/03/03

REPOSITORIES: GEO

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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: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.

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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]

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

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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]

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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 [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