PXD038822

PXD038822 is an original dataset announced via ProteomeXchange.

Title	Combinatorial treatment with PARP and MAPK inhibitors to overcome phenotype switch-driven drug resistance in advanced melanoma
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:02:50.752.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Deena Leslie Pedrioli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-13 23:23:06	ID requested
1	2023-09-08 01:46:23	announced
⏵ 2	2024-10-22 06:02:51	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Melanoma, label-free quantification, LC-MS/MS

Michael O. Hottiger
contact affiliation	Department of Molecular Mechanisms of Disease University of Zurich Winterthurerstr. 190 8057 Zurich, Switzerland
contact email	michael.hottiger@dmmd.uzh.ch
lab head
Deena Leslie Pedrioli
contact affiliation	University of Zürich
contact email	deena.lesliepedrioli@dmmd.uzh.ch
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/09/PXD038822

PRIDE project URI

• PRIDE
  1. PXD038822
     1. Label: PRIDE project
     2. Name: Combinatorial treatment with PARP and MAPK inhibitors to overcome phenotype switch-driven drug resistance in advanced melanoma