Fig. 3. Interpretation of palbociclib response mechanisms.
a, NeST-VNN interpretation of the palbociclib response. Nodes indicate assemblies, whereas node sizes indicate assembly sizes in numbers of proteins. Colors indicate the degree of importance for response prediction: yellow, assemblies with importance > 0.5; red, ‘core’ assemblies, which bring the additional requirement of FDR ≤ 0.1 and exclude redundant assemblies of lesser importance (Jaccard similarity > 0.5). Assemblies containing CDK4 or CDK6 are marked with small black squares. b, Protein interaction network defining the CDK holoenzyme complex I (NeST:110), which contains CDK4 and CDK6. Edges represent biophysical protein–protein associations, with the edge thickness reflecting the strength of the evidence for association. c, Diagram of known functional associations among NeST:110 proteins in the context of cell-cycle progression. The cyclin D–CDK complex inhibits RB1 by phosphorylation, such that it no longer transcriptionally represses genes required for S-phase entry and subsequent DNA replication. d, Scatterplot of assembly importance in the clinical versus cell line contexts (x axis versus y axis). e, Scatterplot of assembly importance in the PDX versus cell line contexts (x axis versus y axis). f, Scatterplot of gene mutation importance in the clinical versus cell line contexts (x axis versus y axis). DREAM, dimerization partner, RB-like, E2F and multivulval class B; MAPK, mitogen-activated protein kinase; RTK, receptor tyrosine kinase; Reg., regulation; tx, transcription; med., mediated; stim., stimulation.