Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combinatorial treatment with PARP and MAPK inhibitors to overcome phenotype switch-driven drug resistance in advanced melanoma

ABSTRACT: Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted drugs such as MAPK inhibitors (MAPKi). Here, using a drug screen targeting chromatin regulators in patient-derived 3D melanoma cell cultures, we discovered that PARP inhibitors are capable of restoring MAPKi sensitivity. This synergy was found to be independent of DNA damage repair pathways and was effective both in vitro and in vivo in patients-derived xenografts. Strikingly, through integrated transcriptomic, proteomic and epigenomic analysis, we discovered that PARPi induces lysosomal autophagy which was accompanied by enhanced mitochondrial lipid metabolism that, ultimately, increased antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, we also found that PARP inhibitors regulated EMT-like phenotype switching by dampening the mesenchymal phenotype via transcriptomic and epigenetic rearrangements. This, in turn, redirected melanoma cells towards a proliferative and, thus, MAPKi-sensitive state. Our study provides a scientific rational for treating patients with PARPi in combination with MAPKi to annihilate acquired therapy resistance.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Deena Leslie Pedrioli

LAB HEAD: Michael O. Hottiger

PROVIDER: PXD038822 | Pride | 2023-09-08

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20190404_02_DLP148_LgxTal2_72hr_neat.raw	Raw
	20190404_10_DLP148_Lgx2_72hr_neat.raw	Raw
	20190404_17_DLP148_LgxTal1_72hr_neat.raw	Raw
	20190404_20_DLP148_Lgx1_72hr_neat.raw	Raw
	20190404_30_DLP148_LgxTal4_72hr_neat.raw	Raw

Items per page:

1 - 5 of 9

Similar Datasets

Combinatorial treatment with PARP and MAPK inhibitors to overcome phenotype switch-driven drug resistance in advanced melanoma

Project description:The prognosis for most patients with advanced malignant melanoma is traditionally very poor, as the disease is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments. Here, using a drug screen targeting chromatin regulators in patient-derived 3D melanoma cell cultures, we discovered that PARP inhibitors are capable of restoring MAPKi sensitivity. This synergy was found to be independent of DNA damage repair pathways and was effective both in vitro and in vivo in patients-derived xenografts. Strikingly, through integrated transcriptomic, proteomic and epigenomic analysis, we discovered that PARPi induces lysosomal autophagy which was accompanied by enhanced mitochondrial lipid metabolism that, ultimately, increased antigen presentation and T-cell cytotoxicity. Moreover, we also found that PARP inhibitors regulated EMT-like phenotype switching by dampening the mesenchymal phenotype via transcriptomic and epigenetic rearrangements. This, in turn, redirected melanoma cells towards a proliferative and, thus, MAPKi-sensitive state. Our study provides a scientific rational for treating patients with PARPi in combination with MAPKi to annihilate acquired therapy resistance

2023-07-01 | GSE221233 | GEO

Transcriptomic data of PC WT cell lines (LNCaP, C4-2B and DU145) compared to PC acquired olaparib-resistance (OR) cell lines

Project description:PARP inhibitors (PARPi) resistance is not well understood in prostate cancer (PC). The aim of the study was to identify new resistance mechanisms in PC by developing acquired olaparib-resistance PC cell lines.

2022-08-12 | E-MTAB-11989 | biostudies-arrayexpress

Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21 (RNA-Seq)

Project description:PARP inhibitors (PARPi) prevent cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternate pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADP-ribosylates DDX21, an RNA helicase that localizes to nucleoli and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites reduce DDX21 nucleolar localization, rDNA transcription, ribosome biogenesis, protein translation, and cell growth. The salient features of this pathway are evident in xenografts in mice and human breast cancer patient samples. Elevated levels of PARP-1 and nucleolar DDX21 are associated with cancer-related outcomes. Our studies provide a mechanistic rationale for efficacy of PARPi in cancer cells lacking defects in DNA repair whose growth is inhibited by PARPi.

2019-07-31 | GSE115760 | GEO

ADP-ribosylation Levels Correlate with Gene Expression Patterns and Clinical Outcomes in Ovarian Cancers

Project description:Inhibitors of nuclear poly(ADP-ribose) polymerase (PARP) enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes.

2019-10-01 | GSE136155 | GEO

Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21 (RIP-Seq)

Project description:PARP inhibitors (PARPi) are thought to control cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternate pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADPribosylates DDX21, an RNA helicase that localizes to the rDNA locus and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites on DDX21 causes a reduction in rDNA transcription, as well as a reduction in ribosome biogenesis, protein translation, and cell growth. Our studies provide mechanistic insights into PARP-1-dependent ADP-ribosylation of DDX21 and its role in ribosome biogenesis. This pathway can be targeted for disruption in cancer cells that lack defects in DNA repair, but exhibit growth inhibition in response to PARPi.

2019-07-31 | GSE115759 | GEO

Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21

2019-07-31 | GSE115761 | GEO

Combined inhibition of MNK signaling and BET proteins reveals TGM2 as a novel vulnerability in melanoma

Project description:Melanoma is the deadliest form of skin cancer. MAPK-targeted therapies (MAPKi) and immune checkpoint inhibitors (ICI) have shown clinical benefit but are limited by resistance mechanisms that remain poorly defined. MNK1/2 inhibitors (MNKi) have shown promising effects in pre-clinical tumor models, particularly in melanoma. Herein, we find that bromodomain and extra-terminal domain protein inhibitors (BETi) in combination with MNKi reduce the proliferation of melanoma cells, including cells with acquired MAPKi resistance. Transcriptomic and proteomic analyses reveal that tissue transglutaminase TGM2 and inhibition of FAK activation are downstream effectors of this combination. We further demonstrate that TGM2 is overexpressed in MAPKi-resistant melanoma cells and that silencing TGM2 inhibits the proliferation of therapy-resistant melanoma cells. Our results introduce TGM2 as a new vulnerability in therapy-resistant melanoma development and suggest that a combination of MNKi and BETi may address the clinical need for novel therapies targeting unresponsive and drug-resistant melanoma.

2024-10-01 | PXD044698 | Pride

Combined Inhibition of MNK Signaling and BET Proteins Reveals TGM2 as a Novel Vulnerability in Melanoma

2024-06-30 | GSE260507 | GEO

Transcriptome profile of biopsies of melanoma patients responder or resistant to MAPKi (MAP-kinases inhibitors)

Project description:To analyse gene expression differences between melanoma patients responder or resistant to MAPKi (MAP-kinases inhibitors).

2022-09-30 | GSE214473 | GEO

Multi-omics characterization of response to PD-1 inhibitors in advanced melanoma

Project description:Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge about the processes involved in response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD1 inhibitors were assessed by high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using network analyses based on probabilistic graphical models to identify those biological processes involved in response to immunotherapy. Additionally, proteins related to overall survival were studied.

2023-09-25 | PXD038155 | Pride

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