Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptional properties of LIG1-heterozygous-knockout (hetKO) vs. LIG1-WT cells in MCF-12A TP53-null and TP53-WT cells

ABSTRACT: Proteogenomic analyses has identified an association between LIG1 (DNA Ligase I) loss and chemotherapy resistance in a subset of triple negative breast cancer (TNBC) enriched for TP53 mutation. Here, we demonstrated that co-occurrence of TP53 mutations and LIG1 loss is associated with upregulated DDR activity, including homologous recombination, likely contributing to reduced platinum sensitivity. Unbiased genetic and monotherapy drug screens identified PARP inhibitiors (PARPi) as a potential treatment for LIG1-depleted tumors, however the increase in sensitivity was modest and lower than levels observed in TNBC models with homologous recombination deficiency. Subsequently, a screen of PARP inhibition in combination with each of 120 clinically relevant DDR inhibitors revealed that PARPi sensitivity in LIG1-loss cells was significantly enhanced by addition of ATR inhibitior (ATRi). Olaparib and ceralasertib demonstrated synergistic cytotoxicity in LIG1-loss cell line models; the combination significantly reduced tumor volume in LIG1-low PDX model compared to either monotherapy, and showed greater ex vivo cytotoxicity in LIG1-low PDX organoids versus LIG1-high control. Hence, this study highlights LIG1-status as a stratification factor into ongoing and future clinical trials of DDR-targeted combinations in TNBCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329371 | GEO | 2026/05/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

MYC inhibition by Omomyc causes DNA damage and overcomes PARPi resistance in breast cancer.

Project description:MYC is dysregulated in most human cancers and is a DNA damage response (DDR) modulator capable of both promoting genomic instability and enhancing DNA repair. Here, we show that Omomyc, the first direct MYC inhibitor to pass a Phase 1 trial, shuts down DDR genes in triple-negative breast cancer (TNBC), causing DDR defects and inducing DNA damage. Since DDR-deficient tumours are currently targeted by PARP inhibitors (PARPi), we tested combinations with Omomyc. We show that Omomyc-induced DNA damage is enhanced by PARPi and that the inhibitors cooperate even in models with intrinsic or acquired PARPi resistance, both in vitro and in vivo. Moreover, using patient-derived models and clinical samples, we reveal a role for MYC as a predictor of PARPi resistance. Overall, our research highlights the opportunity of combining MYC inhibition by Omomyc with PARPi in PARPi-resistant TNBC, where MYC transcriptional activity represents a predictive biomarker of resistance to therapy.

2025-09-26 | GSE309250 | GEO

RNA Sequencing Analysis of control vs KDM4Ai treated cells as a monotherapy or in combination with PARPi

Project description:Leukaemic blasts share common pathological features with other cancers including genome instability and impaired DNA damage response and repair (DDR). The limited efficacy of DDR inhibitors, such as poly (ADP-ribose) polymerase inhibitors (PARPi) as single agents in acute myeloid leukaemia (AML) is partly owing to activation of alternative DDR pathways and cytotoxicity to healthy tissues. Their strengths may lie in combination strategies targeting other essential proteins required for leukaemogenesis. We have identified the histone demethylase, KDM4A, as a critical epigenetic regulator required for AML cell survival. Depletion of KDM4A causes aberrant DDR pathway activation and subsequent DNA damage. We hypothesised that KDM4A inhibitors (KDM4Ai) increase AML cell reliance on specific DDR pathways for survival and may sensitise them to PARPi. We aimed to analyse transcriptional profiling (RNA Seq) changes associated with varying concentrations of KDM4A inhibition in monotherapy and as a combination therapy with a single PARPi treatment following 36hrs treatment. In summary, our study identifies a novel potential therapeutic strategy for AML. KDM4Ai sensitises cells to PARPi through impairing further NHEJ repair and enhancing PARP trapping leading to selective leukaemic cell death. These results warrant future clinical evaluation of this promising combination strategy in AML and other cancers.

2022-12-31 | GSE164437 | GEO

Investigating response to PARP inhibition and androgen receptor pathway inhibition in C4-2B prostate cancer cells

Project description:Use of PARP inhibitors (PARPi) has been shown effective in the management of selected patients with advanced prostate cancer. Still, it is incompletely understood how PARPi work and what mechanisms may enable adaptation and progression. This study utilized RNA-sequencing to understand response to PARP inhibition (olaparib) in regard to both intensity and duration of treatment. PARPi have also been shown to be effective when combined with androgen receptor (AR) pathway inhibitors (ARPi), but much remains unknown regarding the utility of combination regimens. We additionally performed RNA-sequencing to better define transcriptomic changes associated with either monotherapy PARPi (olaparib or talazoparib), monotherapy ARPi (abiraterone or enzalutamide), or combinations (abiraterone + olaparib, enzalutamide + talazoparib).

2026-06-03 | GSE322615 | GEO

Targeting STAT3-FoxO1 axis reverses de novo and acquired PARP inhibitor resistance independent of BRCA status. [Whole-exome seq2]

Project description:PARP inhibition has been approved as a compelling strategy for treating multiple human cancers bearing homologous recombination defects (HRD). However, due to the lack of functional biomarkers of PARPi response beyond known genetic mutations in HRD genes, expanding the potential benefit of PARP inhibitors, as well as the identification of effective therapeutic strategies for treating PARPi-resistant cancers remain urgent unmet needs. Here, we report high levels of FoxO1, either at basal expression or upon induction by PARPi, render both BRCA-proficient (BP) and BRCA-deficient (BD) human cancers resistant to PAPRi via modulating transcriptomic signature regulating DNA damage response (DDR). We further elucidated that PARPi-induced STAT3 activation, which occurred through its attenuated dephosphorylation at Y705, resulted in enhanced FoxO1 transcription via recruiting TOP2A, a downstream target of FoxO1. TOP2A orchestrated STAT3-dependent transcriptional program via facilitating RNA Pol II recruitment to gene promoters, as well as promoter-proximal pausing and pause release. Intriguingly, STAT3 inhibitor exhibits a potent synergistic effect with PARPi in treating BP or BD PAPRi-resistant PDX models across cancer types. Our data highlight a potential role of FoxO1 serving as both predictive and prognostic marker for PARPi treatment, and reveal the potency of combination treatment strategy using STAT3 inhibitor with PARPi in sensitizing PARPi-resistant cancers, regardless of BRCA status.

2025-08-31 | GSE213854 | GEO

Targeting STAT3-FoxO1 axis reverses de novo and acquired PARP inhibitor resistance independent of BRCA status [ChIP-seq]

2025-08-31 | GSE212432 | GEO

Targeting STAT3-FoxO1 axis reverses de novo and acquired PARP inhibitor resistance independent of BRCA status [RNA-seq]

2025-08-31 | GSE212431 | GEO

Targeting STAT3-FoxO1 axis reverses de novo and acquired PARP inhibitor resistance independent of BRCA status [Whole-exome seq]

2025-08-31 | GSE212433 | GEO

Targeting STAT3-FoxO1 axis reverses de novo and acquired PARP inhibitor resistance independent of BRCA status. [Whole-genome seq]

2025-08-31 | GSE213855 | GEO

Aryl Hydrocarbon Receptor suppresses STING-mediated Type I IFN expression in Triple-Negative Breast Cancer

Project description:Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer. Despite decades of intense investigation, treatment options remain limited and rapid recurrence with distant metastases remains a significant challenge in the clinic. Cancer cell-intrinsic production of cytokines such as type I interferons (IFN-I) is a known potent modulator of response to therapy in many cancers, including TNBC, and can influence therapeutic outcome. Here, we report that in TNBC systems the aryl hydrocarbon receptor (AhR) suppresses IFN-I expression via inhibition of Stimulator of Interferon Genes (STING), a key mediator of interferon production. Intratumoral STING activity is essential in mediating the efficacy of PARP inhibitors (PARPi) which are used in the treatment of cancers harboring BRCA-1 deficiency. We find that, in TNBC cells, PARPi treatment activates AhR in a BRCA1 deficiency-dependent manner, thus suggesting the presence of a negative feedback loop aimed at modulating PARPi efficacy. Importantly, our results indicate the combined inhibition of PARP and AhR is superior in elevating IFN-I expression as compared to PARPi-alone. Thus, AhR inhibition may allow for enhanced IFN-I production upon PARPi in BRCA1-deficient breast cancers, most of which are of TNBC origin, and may represent a therapeutically viable strategy to enhance PARPi efficacy.

2024-01-31 | GSE252119 | GEO

Inhibition of USP28 sensitizes ovarian cancer to PARP inhibitor through mediating SOX9 deubiquitination

Project description:PARP inhibitor (PARPi) resistance presents a significant challenge in ovarian cancer treatment, necessitating the development of effective therapeutic strategies to overcome this resistance and improve patient outcomes. Our study demonstrated that elevated expression of SRY-box 9 (SOX9) contributes to olaparib resistance in ovarian cancer. Mechanistically, the deubiquitinating enzyme USP28 was identified as a novel interacting partner of SOX9. USP28 inhibited the ubiquitination and subsequent lysosomal degradation of SOX9, which is mediated by the E3 ubiquitin ligase FBXW7 during olaparib treatment. ChIP-Seq analysis revealed that SOX9 binds to the promoters of key DNA damage response (DDR) genes (SMARCA4, UIMC1, and SLX4), thereby regulating DDR processes in ovarian cancer. Additionally, USP28 promoted olaparib resistance by stabilizing SOX9 protein and enhancing DNA damage repair. Furthermore, the USP28 specific inhibitor AZ1 reduced SOX9 protein stability and increased the sensitivity of ovarian cancer cells to olaparib. In conclusion, targeted inhibition of USP28 promoted ubiquitination-mediated degradation of SOX9, thereby impairing DNA damage repair capabilities and sensitizing ovarian cancer cells to PARPi. These findings elucidate the underlying mechanisms of PARPi resistance in ovarian cancer and suggest the potential efficacy of combining USP28 inhibitors with PARPi to overcome this resistance.

2025-04-23 | GSE271296 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data