Figure 5: Functional coordination between TME-mediated (de novo) and acquired IR.

(a) Diagram of three types of drug resistance mechanisms for kinase activity profile: parental cells after co-culture with stromal (HK) cells (de novo DR), IR cells after chronic ibrutinib exposure in cell suspension (acquired DR) and IR cells selected with drug (chronic ibrutinib exposure) in the presence of stroma (combined DR). Parental cells in suspension are as reference. (b) Significant increased kinase ATP-binding changes in de novo DR cells (left), acquired DR cells (middle) and combined DR (right). Parental cells maintained in suspension were used as the control reference population (Jeko-1, HBL-2 and SP49). Kinome trees reproduced courtesy of Cell Signaling Technology. (c) Principal component analysis (PCA) of kinomes of parental/sensitive, de novo IR (TME-mediated), acquired IR and IR selected while adherent to TME stroma (combined IR) cells, which correlate with the first two principal components. (d) KEGG pathway enrichment analysis revealed highly significant pathways (−log P value>2) in the three types of IR kinome. Parental cells maintained in suspension were used as the control reference population. There is a greater overlap between acquired IR and combined IR relative to de novo IR. See also Supplementary Fig. 5.