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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]

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

PROVIDER: PRJNA1230750 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32548235_1.fastq.gz	Fastqsanger.gz
	SRR32548235_2.fastq.gz	Fastqsanger.gz
	SRR32548236_1.fastq.gz	Fastqsanger.gz
	SRR32548236_2.fastq.gz	Fastqsanger.gz
	SRR32548237_1.fastq.gz	Fastqsanger.gz

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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

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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]

Project description: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 [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]

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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]

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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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.

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

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ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (ATAC-seq)

Project description:The response to Poly (ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair mechanisms and the abundance of lesions that trap PARP enzymes on chromatin. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR based screen, we identify the PAR-binding Snf2-like ATPase, ALC1 as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of BRCA mutant cells and enhanced their sensitivity to PARPi by up to 250-fold, while overcoming several known resistance mechanisms. ALC1 loss was not epistatic to other repair pathways that execute the PARPi response. Instead, ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of repair factors. This resulted in an accumulation of replication associated DNA damage and a reliance on HR. These findings establish PAR-dependent chromatin remodeling as a mechanistically distinct aspect of PARPi responses, implicating ALC1 inhibition as a new approach to overcome therapeutic resistance in HR-deficient cancers.

2020-12-02 | GSE150955 | GEO

ALC1 and PARP activities coordinate chromatin accessibility and viability in homologous recombination deficient cells (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]

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