PXD026557

PXD026557 is an original dataset announced via ProteomeXchange.

Title	Proteomic and phosphoproteomics profiling depict drug addiction mechanisms in BRAFi-resistant melanoma
Description	Acquired resistance to MAPK inhibitors limits the clinical efficacy in melanoma treatment. We and others have recently shown that BRAF inhibitors (BRAFi)-resistant melanoma cells can develop a dependency on the therapeutic drugs to which they have acquired resistance, creating a vulnerability for these cells that can potentially be exploited in cancer treatment. In drug addicted melanoma cells, it was shown that this induction of cell death was preceded by a specific ERK2-dependent phenotype switch, however, the underlying molecular mechanisms are largely lacking. To increase the molecular understanding of this drug dependency, we applied a mass spectrometry-based proteomic approach on BRAFi-resistant BRAFMUT 451Lu cells, in which ERK1, ERK2 and JUNB were silenced separately using CRISPR–Cas9. Inactivation of ERK2 and, to a lesser extent, JUNB prevents drug addiction in these melanoma cell while, conversely, knock out of ERK1 fails to reverse this phenotype, showing a response similar to control cells. Our analysis reveals that ERK2 and JUNB share comparable proteome responses dominated by reactivation of cell division. Importantly, we find that EMT activation in drug addicted melanoma cells upon drug withdrawal is affected by silencing ERK2 but not ERK1. Moreover, transcription factor (regulator) enrichment shows that PIR acts as an effector of ERK2 and phosphoproteome analysis reveals that silencing of ERK2 but not ERK1 leads to amplification of GSK3 kinase activity. Our results depict possible mechanisms of drug addiction in melanoma, which may provide a guide for strategies in drug-resistant melanoma.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-17_09:14:47.095.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bohui Li
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-07 22:56:42	ID requested
⏵ 1	2022-02-17 09:14:47	announced

Li B, Kong X, Post H, Raaijmakers L, Peeper DS, Altelaar M, Proteomics and Phosphoproteomics Profiling of Drug-Addicted BRAFi-Resistant Melanoma Cells. J Proteome Res, 20(9):4381-4392(2021) [pubmed]

submitter keyword: Melanoma

BRAF resistant

Proteomics

Phosphoproteomics

ERK2/MAPK1

ERK1/MAPK3

EMT

Maarten Altelaar
contact affiliation	1 Biomolecular Mass Spectrometry and Proteomics Group, Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, The Netherlands. 2 Netherlands Proteomics Center, Padualaan 8, 3584 CH Utrecht, The Netherlands 3 Mass Spectrometry and Proteomics Facility, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
contact email	m.altelaar@uu.nl
lab head
Bohui Li
contact affiliation	Biomolecular Mass Spectrometry and Proteomics Group, Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, The Netherlands.
contact email	libohui123@gmail.com
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/2022/02/PXD026557

PRIDE project URI

• PRIDE
  1. PXD026557
     1. Label: PRIDE project
     2. Name: Proteomic and phosphoproteomics profiling depict drug addiction mechanisms in BRAFi-resistant melanoma