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Mapping the Genetic Interaction Network of PARP inhibitor Response

ABSTRACT: Mapping the Genetic Interaction Network of PARP inhibitor Response

PROVIDER: PRJNA1196842 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31677610_1.fastq.gz	Fastqsanger.gz
	SRR31677610_2.fastq.gz	Fastqsanger.gz
	SRR31677611_1.fastq.gz	Fastqsanger.gz
	SRR31677611_2.fastq.gz	Fastqsanger.gz
	SRR31677612_1.fastq.gz	Fastqsanger.gz

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Mapping the Genetic Interaction Network of PARP inhibitor Response

Project description:Genetic interactions have long informed our understanding of the coordinated proteins and pathways that respond to DNA damage in mammalian cells, but systematic interrogation of the genetic network underlying this system has yet to be achieved. Towards this goal, we measured 147,153 pairwise interactions among genes implicated in PARP inhibitor (PARPi) response with and without exposure to PARPi. By applying an analytical framework we defined differential genetic interactions at scale, identified novel interactions belonging to different interaction categories, and revealed PARP1-trapping as a common mode of sensitization of PARPi across genetic backgrounds. We uncovered the minimally characterized gene, AUNIP, while not essential for genome stability under normal conditions, plays a key role in repairing PARPi induced DNA damage together with FA pathway genes and is antagonized by the BRCA1-A complex. Our work thus establishes a foundation for mapping differential genetic interactions in mammalian cells and provides a comprehensive resource for future studies of DNA repair and PARP inhibitors.

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Amplification of mutant BRCA2 gene confers resistance to PARP inhibitor

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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.

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Project description:Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.

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