Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A pan-cancer study to identify and characterize synthetic lethal drugs in BAP1-deficient cancers

ABSTRACT: BRCA-1 Associated Protein (BAP1) is a deubiquitinating enzyme that acts as a tumour suppressor. Inactivating mutations in the BAP1 gene have been identified in many cancers including cholangiocarcinoma, hepatocellular carcinoma, mesothelioma, uveal melanoma and renal cell carcinoma. Current standard therapeutic approaches for BAP1-deficient tumours are not particularly promising, contributing to poor overall survival and disease-free survival rates. Here, we found BAP1 to mediate the turnover of the key proteins in the DNA nucleotide excision repair (NER) pathway, and therefore promotes DNA repair. Importantly, we demonstrate that the loss of functional BAP1 sensitise tumour cells to LSD1 inhibitor, SP2509, in vitro and in vivo, through further impairment of NER efficiency. When used in combination with PARP1 inhibitor, Olaparib, we show that a synergistic drug combination response is achieved. Overall, our study identifies a drug combination approach that has the potential to be exploited clinically to target BAP1 deficient tumours.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Radoslaw Mikolaj Sobota

PROVIDER: PXD028470 | JPOST Repository | Thu Sep 15 00:00:00 BST 2022

REPOSITORIES: jPOST

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20190821_JH_EV_Ubi_TR1.raw	Raw
	20190821_JH_MUT_Ubi_TR1.raw	Raw
	20190821_JH_WT_Ubi_TR1.raw	Raw
	20190902_JH_EV_Ubi_TR2.raw	Raw
	20190902_JH_EV_Ubi_TR3.raw	Raw

Items per page:

1 - 5 of 20

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair

Project description:Glioblastoma (GBM) is the most lethal brain tumour that occurs in adults and treatment for GBM has been largely unsuccessful. Ionizing radiation (IR) and chemotherapeutic agents are employed as standard of care treatment for GBM patients and both result in DNA damage. Previous data identified phosphorylation of PTEN at tyrosine 240 (pY240) in samples from patients with recurrent GBM receiving standard of care treatment and was associated with decreased overall survival. Here we demonstrate that pY240 PTEN that was triggered by FGFR2 signaling, enhanced DNA repair by facilitating the loading of PTEN onto chromatin through its interaction with KI-67 and subsequent recruitment of the DNA repair protein, RAD51, to sites of DNA damage. Thus, tumour cells with pY240 PTEN are efficient at repairing DNA damage which would be predicted to result in resistance to therapy. These findings suggest the FGFR-pY240 PTEN-DNA repair mechanism as a therapeutic target for enhancing GBM therapy.

2017-08-07 | MSV000081423 | MassIVE

Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma

Project description:The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. We performed a high‐throughput, combination chromatin‐modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4‐mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.

2024-11-13 | GSE281811 | GEO

Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study

Project description:Single Center, open label, Phase I-II trial designed to test the safety and efficacy of the combination of Ataluren and Pembrolizumab for the treatment of metastatic mismatch repair deficient and proficient colorectal adenocarcinoma and metastatic mismatch repair deficient endometrial carcinoma.

| 2310512 | ecrin-mdr-crc

Genome-wide microRNA expression profiling identifies miR-9-3 and miR-193a as targets for DNA methylation in non-small cell lung cancers

Project description:Purpose: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on microRNA (miRNA) silencing in non-small cell lung cancers (NSCLC). Experimental Design: We performed microarray expression analyses of 856 miRNAs in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2Â´-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. MiRNA methylation was determined in 11 NSCLC cell lines and in primary tumors and corresponding non-malignant lung tissue samples of 101 stage I-III NSCLC patients. Results: By comparing microarray data of untreated and drug treated A549 cells, we identified 33 miRNAs whose expression was upregulated after drug treatment and which are associated with a CpG island. Thirty (91%) of these miRNAs were found to be methylated in at least 1 of 11 NSCLC cell lines analysed. Moreover, miR-9-3 and miR-193a were found to be tumor-specifically methylated in NSCLC patients. We observed a shorter disease-free survival of miR-9-3 methylated lung squamous cell carcinoma (LSCC) patients compared to miR-9-3 unmethylated LSCC patients by multivariate analysis (HR = 3.8, 95% CI = 1.3 to 11.2, p = 0.017) and a shorter overall survival of miR-9-3 methylated LSCC patients compared to miR-9-3 unmethylated LSCC patients by univariate analysis (p = 0.013). Conclusions: Overall, our results suggest that methylation is an important mechanism for inactivation of certain miRNAs in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in LSCC patients. MiRNA expression (LC Sciences, mirBASE12) was analyzed before and after treatment of A549 cells with 5-aza-2Â´-deoxycytidine (Aza-dC) and a combination of Aza-dC and trichostatin A (TSA). Experiments were performed in duplicates.

2012-03-13 | E-GEOD-31579 | biostudies-arrayexpress

Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177)

Project description:In this study, participants with stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) colorectal carcinoma (CRC) will be randomly assigned to receive either pembrolizumab or the Investigator’s choice of 1 of 6 standard of care (SOC) chemotherapy regimens for the treatment of advanced colorectal carcinoma. The primary study hypothesis is that pembrolizumab will prolong progression-free survival (PFS) or overall survival (OS) compared to current SOC chemotherapy.

| 2199120 | ecrin-mdr-crc

Project description:Identification of tumour-infiltrating myeloid subsets associated with overall survival in lung squamous cell carcinoma

| PRJNA884683 | ENA

p97/VCP inhibition radiosensitises cancer cells through excessive MRE11-dependent DNA end resection

Project description:Cancer cells are under constant proteotoxic stress and have an increased genomic instability. They therefore rely on upregulation of protein homeostasis and the DNA damage response (DDR) for survival. The ubiquitin-dependent ATPase p97 is a central component of the ubiquitin-proteasome degradation system (UPS), involved in both protein homeostasis and DDR. p97 is overexpressed in many tumours and its overexpression correlates with poor prognosis in patients. To explore the concept of cancer cell killing by combined targeting of DDR and proteostasis, we induced DNA damage by ionising radiation (IR) and inhibited proteostasis by CB-5083, a specific small molecule inhibitor of p97, in bladder cancer cell lines and a mouse xenograft model. Combined therapy induced radiosensitivity and supressed xenograft tumour growth. Mechanistically, inactivation of the p97 ATPase activity results in proteotoxic accumulation of the nuclease MRE11 at the sites of IR-induced DNA lesions. This leads to excessive formation of single-stranded DNA (ssDNA), inhibition of HR, reliance on SSA for DSB repair and synthetic lethality after IR exposure in non-homologous end-joining-defective tumour cells such as those in muscle-invasive bladder carcinoma patients

2021-05-18 | PXD016279 | Pride

RNA microarray of human cervical cancer cell line HeLa treated with imatinib, mitoxantrone or mitoxantrone+imatinib combination against untreated controls

Project description:Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which are detrimental to the cell, if not repaired. This repair process requires high-fidelity functional homologous recombination or error-prone non-homologous recombination. If either of these pathways is targeted, the compensatory pathway may rescue the cells and induce treatment resistance. c-Abl is a protein tyrosine kinase that is involved in cell differentiation, cell division, cell adhesion, and stress response including DNA damage induced stress. Here we used a low dose topoisomerase II inhibitor mitoxantrone to induce DNA damage and c-Abl kinase inhibitor imatinib in combination and studied the drug effects at transcriptomic level. The microarray data suggests that DNA repair, particularly homologous recombination, is downregulated together with alterations in cell cycle regulation. The data prompted to further validation assays on functional level which are shown in the original publication.

2021-09-22 | E-MTAB-9475 | biostudies-arrayexpress

Synthetic essentiality of thymine DNA glycosylase in p53-deficient cancer [CUT&Tag]

Project description:Thymine DNA Glycosylase (TDG) is a versatile protein involved in DNA mismatch repair, DNA demethylation, and transcriptional regulation. Here, we identify TDG as a synthetic essential effector in p53-deficient tumours. We found that deletion of TDG inhibits cell proliferation specifically in p53-deficient cancer cells. Using a genetically engineered mouse model of lung adenocarcinoma (LUAD), we demonstrate that depletion of TDG suppresses tumour growth in the p53-deficient context. Notably, A novel and selective inhibitor developed to disrupt the DNA binding activity of TDG exhibits therapeutic efficacy against p53-deficient tumours in both cellular and xenograft models. Mechanistically, TDG coordinates with p53 to orchestrate the transcription of RNA helicase DHX9, which functions to eliminate dsRNA. Depletion of TDG in p53-deficient cells results in the downregulation of DHX9 and aberrant cytoplasmic double-strand (dsRNA) accumulation derived from Alu elements, subsequently activating the RIG-I/MDA5-MAVS mediated antiviral response. Moreover, single-cell RNA-sequencing analysis revealed the depletion of TDG in p53-deficient tumours facilitates the recruitment of tumour-infiltrating lymphocytes. We observed that TDG inhibition combined with immune checkpoint blockade (ICB) achieved a strong synergistic anti-tumour effect in p53-deficient tumours. This study highlights the function of TDG in maintaining p53-deficient tumour growth and provides an alternative therapeutic target for p53-deficient cancers.

2024-06-21 | GSE236718 | GEO

Synthetic essentiality of thymine DNA glycosylase in p53-deficient cancer [scRNA-seq]

2024-06-21 | GSE236727 | GEO