101 (Phospho)proteomics biomarkers for sunitinib response in RCC Figure 2. Proteome analysis of patients with RCC sensitive or resistant to sunitinib a. Supervised clustering analysis of the proteome. Supervised cluster analysis of differentially expressed proteins (n = 173) in tumor tissue lysates of 25 patients (17 sensitive and 8 resistant to sunitinib) shows one cluster of 13 sensitive patients and a mixed cluster of 8 resistant plus 4 sensitive patients. Filters: p <0.05, |FC|>2, ≥50% data presence in the highest group. For clustering, Euclidean distance and Ward’s linkage method were used. Histology = histological subtype as determined by pathologist review; PFS = progression free survival in months; NE = not evaluable. b. Overview of the data filtering steps applied in protein analysis, including the effect of each filter on the total number. c. Protein interaction networks. Using STRING and visualization in Cytoscape, major functional protein clusters, corresponding to either sensitive or resistant patients, are shown. Nodes correspond to upregulated proteins and edges symbolize physical or functional associations. Green clusters represent proteins upregulated in lysate of tumors sensitive to sunitinib and purple clusters represent proteins upregulated in lysate of tumors primary resistant to sunitinib. Representative GO terms identified by BiNGO analysis in both sensitive and resistant samples are listed together with the number of proteins (nodes) per cluster. All proteins in this figure are filtered for p < 0.05 & FC > 2 & ≥ 50% data presence in the group with highest abundance. EXPLORATION OF PHOSPHO-SITE AND PROTEIN SIGNATURE CANDIDATES IN PUBLICLY AVAILABLE TRANSCRIPTOME DATA To confirm our findings from this small cohort of patients, we searched the literature for a comparable independent cohort describing ideally phosphoproteome- or proteome-based profiles or an upstream RNA analysis in relation to clinical outcomes of patients treated with sunitinib. We were able to compare our findings to the results of a cohort by Beuselinck et al. describing the transcriptome in relation to sunitinib response44. Comparing five primary 4
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