Ontology highlight
ABSTRACT:
PROVIDER: PRJEB33877 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3466930_1.fastq.gz | Fastqsanger.gz | |||
| ERR3466930_2.fastq.gz | Fastqsanger.gz | |||
| ERR3466940_1.fastq.gz | Fastqsanger.gz | |||
| ERR3466940_2.fastq.gz | Fastqsanger.gz | |||
| ERR3466950_1.fastq.gz | Fastqsanger.gz |
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Project description:Oncogenic mutations in the metabolic enzyme isocitrate dehydrogenase 1 and 2 (IDH1/2) have been found in a number of liquid and solid tumors. Their pathogenic mechanism of action involves production of 2-hydroxyglutarate (2HG), an oncometabolite that acts in part by inhibiting members of a family of dioxygenases that modulate chromatin dynamics. Recent work has suggested that mutant IDH (mIDH) and 2HG also impact sensitivity to inhibitors of poly-ADP ribose polymerases (PARP) but the molecular basis for this sensitivity is unclear. Unlike PARP inhibitor-sensitive BRCA1/2 tumors which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack mutational signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to heterochromatin-dependent slowing of DNA replication and increased replication stress, resulting in DNA double strand breaks. This replicative stress manifests as replication fork slowing but the breaks are repaired without a significant increase in the cellular mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-ADP ribosylation. Treatment with PARP inhibitors restores replication fork speed but results in incomplete repair of DNA breaks. These findings provide evidence of a requirement for PARP in the replication of heterochromatin and further validate PARP as a potential therapeutic target in IDH-mutant tumors.
2023-08-28 | GSE211592 | GEO
Project description:Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in cancer. HR-deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of HR deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Using whole exome and genome sequencing data, we found that a significant subset of GEA, but very few colorectal adenocarcinomas, show evidence of HR deficiency by mutational signature analysis (HRD score). High HRD gastric cancer cell lines demonstrated functional HR deficiency by RAD51 foci assay and increased sensitivity to platinum chemotherapy and PARP inhibitors. Of clinical relevance, analysis of three different GEA patient cohorts demonstrated that platinum treated HR deficient cancers had better outcomes. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by two photoproduct repair assays. Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors.
2024-02-23 | GSE256301 | GEO
Project description:Preclinical data support the investigation of PARP inhibitors in other neoplasms exhibiting homologous recombination deficiency (HRD) as monotherapy as well as in combination with chemotherapy. However，in colorectal cancer (CRC), the role of HRD alterations is mostly unknown. This study aims to explore the the Efficacy and Safety of Fluzoparib combined with Irinotecan in the Second-line treatment of HRD alterations metastatic colorectal cancer.
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Project description:Inhibitors of PARP (PARPis) represent the first clinically approved anticancer agents targeting the DNA damage response. They have been approved as monotherapy and/or in combination and maintenance settings in different tumor types, including high-grade ovarian carcinomas. Their efficacy was first underlined in cells with functional inactivation of BRCA1 and BRCA2 genes and this strong preclinical evidence prompted their clinical development in tumors with BRCA1/BRCA2 mutations. It was later demonstrated that PARPis were very effective in tumors displaying deficiency in homologous recombination (HR) repair beyond BRCA1 and BRCA2 loss of function. In addition, evidence from randomized clinical trials supports their efficacy also in tumors with intact HR repair, although to a lesser extent.
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Project description:Colorectal Cancer ranks third among the most frequent malignancies representing a leading cause of cancer-related death worldwide. The constant improvement in the "continuum of care" of metastatic colorectal cancer (mCRC) patients led to a median overall survival of about 30-36 months.
Due to the cumulative toxicities of first-line combinations of chemotherapy and biological agents, discontinuation or intermittent chemotherapy or maintenance strategies have been investigated in clinical trials. After a 4 to 6-month induction treatment with bevacizumab plus doublet or triplet regimens, a fluoropyrimidine plus bevacizumab is regarded as the optimal maintenance regimen. Little evidence is available on the role of maintenance with anti-EGFR agents.
A recent systematic review and network meta-analysis of 12 relevant randomized clinical trials comprising 5540 patients with mCRC showed that a maintenance strategy with a fluoropyrimidine, with or without the addition of bevacizumab, is preferred. However, given the lack of a clear overall survival benefit, shared decision-making should include observation as an acceptable alternative.
Poly(ADP)-ribose polymerase (PARP) inhibitors are now approved for breast, ovarian and pancreatic cancers. Evidence suggests that PARP inhibitors are more effective in tumors harboring homologous recombination DNA damage repair (HRR) deficiency and platinum sensitivity may be used a surrogate marker of HRD and therefore of PARP-inhibitors efficacy. An extensive Next Generation Sequencing analysis revealed that 15% of mCRC samples harbors mutations in genes involved in the HRR pathway. Several clinical trials are ongoing to test PARP inhibitors either alone or in combination in mCRC patients. The originality of this trial is to investigate PARPi in the maintenance setting.
Pre-clinical evidence showed that PARP blockade after initial oxaliplatin response delayed disease progression in mCRC carrying Kirsten Rat Sarcoma and BRAF mutations, suggesting that maintenance treatment with PARP inhibitors warrants further clinical investigation in mCRC patients who respond to oxaliplatin-containing induction treatment.
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Project description:HS-10502 is a Poly(ADP-ribose) polymerase 1 (PARP1)-specific selective inhibitor. The purpose if this study is to assess the safety, tolerability, pharmacokinetics (PK), and efficacy of HS-10502 in subjects with homologous recombination repair (HRR) gene mutant or homologous recombination deficiency (HRD) positive advanced solid tumors.
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Project description:A subset of small cell lung cancer (SCLC) shows a clinical response to PARP inhibitors (PARPi) despite being proficient in homologous repair pathways. However, the underlying mechanism(s) of PARPi sensitivity is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in a large panel of molecularly annotated patient-derived SCLC lines. We found that the toxicity of PARPi in SCLC is explained by the PARPi-induced degradation of key lineage-specific oncoproteins including ASCL1, NEUROD1, POU2F3, KDM4A, and KDM5B. Biochemical experiments showed that PARPi-induced activation of E3 ligases (e.g., HUWE1 and RNF8) mediated the ubiquitin-proteasome system (UPS)-dependent degradation of these oncoproteins. Interestingly, although PARPi resulted in a general DNA damage response, this signal is sensed by different SCLC cell lines to generate a cell-specific response. The dissection of the cell-specific oncoprotein degradation response led to the identification of potentially predictive biomarkers for PARPi in SCLC. The combination of PARPi and agents targeting these pathways led to dramatically improved cytotoxicity in SCLC. PARPi-induced degradation of lineage-specific oncoproteins therefore represents a novel mechanism to explain the efficacy of PARPi in tumors without homologous recombination deficiency.
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Project description:A subset of small cell lung cancer (SCLC) shows a clinical response to PARP inhibitors (PARPi) despite being proficient in homologous repair pathways. However, the underlying mechanism(s) of PARPi sensitivity is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in a large panel of molecularly annotated patient-derived SCLC lines. We found that the toxicity of PARPi in SCLC is explained by the PARPi-induced degradation of key lineage-specific oncoproteins including ASCL1, NEUROD1, POU2F3, KDM4A, and KDM5B. Biochemical experiments showed that PARPi-induced activation of E3 ligases (e.g., HUWE1 and RNF8) mediated the ubiquitin-proteasome system (UPS)-dependent degradation of these oncoproteins. Interestingly, although PARPi resulted in a general DNA damage response, this signal is sensed by different SCLC cell lines to generate a cell-specific response. The dissection of the cell-specific oncoprotein degradation response led to the identification of potentially predictive biomarkers for PARPi in SCLC. The combination of PARPi and agents targeting these pathways led to dramatically improved cytotoxicity in SCLC. PARPi-induced degradation of lineage-specific oncoproteins therefore represents a novel mechanism to explain the efficacy of PARPi in tumors without homologous recombination deficiency.
2024-01-26 | PXD029968 | Pride
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.
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