Ontology highlight
ABSTRACT:
PROVIDER: PRJNA588424 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10418658_1.fastq.gz | Fastqsanger.gz | |||
| SRR10418658_2.fastq.gz | Fastqsanger.gz | |||
| SRR10418659_1.fastq.gz | Fastqsanger.gz | |||
| SRR10418659_2.fastq.gz | Fastqsanger.gz | |||
| SRR10418660_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 14 |
Similar Datasets
Project description:PARP inhibitor and platinum based drugs such as cisplatin are promising therapies for triple negative breast cancer and exploit the deficiencies in BRCA1 or BRCA2, or homologous recombination repair defects. However, PARP inhibitor resistance is proven to be a major clinical problem. Acquired PARP inhibitor resistance has been linked with co-resistance to platinum-based drugs. To determine how acquired olaparib resistance affects cisplatin response and whether this is influenced by their BRCA1 status, we performed RNAseq transcriptome analysis of isogenic triple negative breast cancer models of olaparib resistance with normal and mutant BRCA1.
2021-07-22 | GSE165914 | GEO
Project description:BRCA1 deficiencies cause breast, ovarian and other cancers, and render tumours hypersensitive to PARP-inhibitors. To understand resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP-inhibitors. Thus, we identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, termed “Shieldin” (SHLD1/2), with FAM35A interacting with single-stranded DNA via its C-terminal OB-fold region. We establish that Shieldin promotes DNA double-strand break (DSB) end-joining, acting as the downstream effector of 53BP1/RIF1/MAD2L2 to restrict DSB resection and counteract homologous recombination in BRCA1-deficient cells by antagonising BRCA2/RAD51 loading. Notably, Shieldin inactivation further sensitises BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.
2018-05-31 | PXD009830 | Pride
Project description:The poly (ADP-ribose) polymerases (PARPs) inhibitors are an exciting new class of agents that have shown efficacy in treating various cancers, especially these harboring BRCA1/2 mutations. The cancer associated BRCA1/2 mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPi) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting accumulation of toxic DSBs. Unfortunately, PARP inhibitor (PARPi) resistance is common and develops through multiple mechanisms. Restoration of HR and/or stabilizing replication forks are two major mechanisms of PARPi resistance in BRCA1/2-mutated cells. To further understand the mechanisms of drug resistance to PARPi, we undertook an unbiased approach with a CRISPR-pooled library to screen new genes whose loss-of-function confers resistance to PARPi olaparib. We identified ZNF251, a transcription factor, and confirmed its loss-of-function led to the PARPi resistance in BRCA1-mutated breast and ovarian cancer lines. Elevated activities of both HR and non-homologous end joining (NHEJ) repair were detected in cancer cells harboring BRCA1 mutation and ZNF251 deletion (BRCA1mut+ZNF251del) and were associated with enhanced expression of RAD51 and Ku70/Ku80, respectively. Furthermore, we showed that DNA-PKcs inhibitor restored sensitivity of BRCA1mut+ZNF251del cells to PARPi. Taken together, our study identified a novel gene whose loss of function conferred resistance to PARPi, providing new insight into signaling pathways that contribute to acquired resistance in BRCA1-mutated breast and ovarian cancers.
2023-05-31 | GSE205221 | GEO
Project description:Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiple in vitro models of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but not BRCA1/2 mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of their BRCA1/2 status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC
2023-01-22 | GSE223011 | GEO
Project description:NASP modulates histone turnover to drive PARP inhibitor resistance
| PRJNA1244778 | ENA
Project description:NASP modulates histone turnover to drive PARP inhibitor resistance
| PRJEB86492 | ENA
Project description:Poly(ADP-ribose) polymerase (PARP) inhibitors show efficacy in breast cancer patients with BRCA1/2 mutations. However, certain BRCA1 single nucleotide polymorphisms (SNPs) may alter protein function without complete loss of activity. This study investigates whether specific BRCA1 SNPs within the DNA binding domain affect cellular sensitivity to PARP inhibition. We used breast cancer cell lines with heterozygous BRCA1 SNPs (CAMA-1: rs799917, rs16941, rs16942, rs1799966) or wild-type BRCA1 (T47D). Cell viability was assessed following olaparib treatment using MTT assay. Transcriptome sequencing and functional enrichment analyses were performed. CAMA-1 cells exhibited significantly enhanced olaparib sensitivity compared to T47D cells, with viability reduced to 45% versus 75% at 50 μM after 72 hours (p<0.001). Transcriptome analysis revealed 6,978 differentially expressed genes, with enrichment in DNA binding, transcriptional regulation, and cellular degradation pathways, suggesting conditional haploinsufficiency under PARP inhibition stress. Heterozygous BRCA1 SNPs in the DNA binding domain confer increased PARP inhibitor sensitivity without pathogenic mutations. This suggests potential expansion of PARP inhibitor therapy to patients with specific BRCA1 polymorphisms, representing a novel biomarker for personalized breast cancer treatment.
2026-06-30 | GSE315381 | GEO
Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information.
2014-01-24 | GSE54268 | GEO
Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information.
2014-01-24 | GSE54267 | GEO
Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information.
2014-01-24 | GSE54266 | GEO