Proteomics

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Analysis of Amino Acid Variants in Malignant Melanoma Cells Resistant to BRAF inhibition


ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF-X, Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Nicolas Nalpas  

LAB HEAD: Prof. Dr. Boris Macek

PROVIDER: PXD018305 | Pride | 2021-11-04

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20190514_MaS_RUNX1_IP_02.raw Raw
20190719_MaS_KB_OE_Runx1_R1.raw Raw
20190719_MaS_KB_OE_Runx1_R2.raw Raw
20191017_MaS_A375S_proteome_input_01.raw Raw
20191017_MaS_A375S_proteome_input_02.raw Raw
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Publications

Proteogenomics Reveals Perturbed Signaling Networks in Malignant Melanoma Cells Resistant to BRAF Inhibition.

Schmitt Marisa M   Sinnberg Tobias T   Bratl Katrin K   Zittlau Katharina K   Garbe Claus C   Macek Boris B   Nalpas Nicolas C NC  

Molecular & cellular proteomics : MCP 20211019


Analysis of nucleotide variants is a cornerstone of cancer medicine. Although only 2% of the genomic sequence is protein coding, mutations occurring in these regions have the potential to influence protein structure or modification status and may have severe impact on disease aetiology. Proteogenomics enables the analysis of sample-specific nonsynonymous nucleotide variants with regard to their effect at the proteome and phosphoproteome levels. Here, we developed a proof-of-concept proteogenomic  ...[more]

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