PXD018305

PXD018305 is an original dataset announced via ProteomeXchange.

Title	Analysis of Amino Acid Variants in Malignant Melanoma Cells Resistant to BRAF inhibition
Description	Analysis of patient-specific nucleotide variants is a cornerstone of personalised medicine. Although only 2% of the genomic sequence is protein-coding, mutations occurring in these regions have the potential to influence protein structure and may have severe impact on disease aetiology. Of special importance are variants that affect modifiable amino acid residues, as protein modifications involved in signal transduction networks cannot be analysed by genomics. Proteogenomics enables analysis of proteomes in context of patient- or tissue-specific non-synonymous nucleotide variants. Here, we developed a proteogenomics workflow and applied it to study resistance to serine/threonine-protein kinase B-raf (BRAF) inhibitor (BRAFi) vemurafenib in malignant melanoma cell line A375. This approach resulted in high identification and quantification of non-synonymous nucleotide variants and (phospho)proteins. We integrated multi-omic datasets to reconstruct the perturbed signalling networks associated with BRAFi resistance and to predict drug therapies with the potential to disrupt BRAFi resistance mechanism in A375 cells. Notably, we showed that aurora kinase A (AURKA) inhibition is effective and specific against BRAFi resistant A375 cells. Furthermore, we investigated nucleotide variants that interfere with protein post-translational modification (PTM) status and potentially influence cell signalling. Mass spectrometry (MS) measurements confirmed variant-driven PTM changes in 12 proteins; among them was the runt-related transcription factor 1 (RUNX1) displaying a variant on a known phosphorylation site S(Ph)276L. We confirmed the loss of phosphorylation site by MS and demonstrated the impact of this variant on RUNX1 interactome.
HostingRepository	PRIDE
AnnounceDate	2021-11-04
AnnouncementXML	Submission_2021-11-04_00:47:51.389.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nicolas Nalpas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF; Orbitrap Exploris 480; Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2020-03-31 02:25:49	ID requested
⏵ 1	2021-11-04 00:47:52	announced

Schmitt M, Sinnberg T, Bratl K, Zittlau K, Garbe C, Macek B, Nalpas NC, Proteogenomics Reveals Perturbed Signaling Networks in Malignant Melanoma Cells Resistant to BRAF Inhibition. Mol Cell Proteomics, 20():100163(2021) [pubmed]

submitter keyword: Proteogenomics, Cancer, Melanoma, BRAFi Resistance, Phosphorylation, Mass Spectrometry, Nucleotide Sequencing

Prof. Dr. Boris Macek
contact affiliation	Chair, Quantitative Proteomics Director, Proteome Center Tuebingen Interfaculty Institute for Cell Biology University of Tuebingen Auf der Morgenstelle 15 72076 Tuebingen Germany
contact email	boris.macek@uni-tuebingen.de
lab head
Nicolas Nalpas
contact affiliation	Tuebingen University
contact email	nalpas.nicolas@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD018305
     1. Label: PRIDE project
     2. Name: Analysis of Amino Acid Variants in Malignant Melanoma Cells Resistant to BRAF inhibition