The perturbed functional sub network EX 527 SEN0014196 of apoptosis is disrupted by inhibition of ABL2, MLTK, LYN and MAPK14. These kinases are not annotated themselves as,induction of apoptosis by intracellular signals, but act at the periphery of the uniform functional sub network. K562 cells express ABL1, a central node of the network, and its fusion protein BCR ABL. High amounts of BCR ABL hide specific ABL1 detection with mass spectrometry. However, western blots proved ABL1 as a competed target of bafetinib in K562. Hence, the score of perturbation underestimates the impact of bafetinib on apoptosis in CML. The impact of bafetinib on apoptosis in CML is manifested with 5 targeted kinases at the periphery.
The method strongly prefers networks which are attacked by several high affinity drug targets. In theory, a single perturbation might be enough to significantly interfere with a biological function. However, biological signaling networks are often highly redundant thus requiring perturbation PF-04217903 at several points in order to observe an effect. Hence, promiscuous drugs like dasatinib are very successful in CML and other cancers and the multi targeted networks are likely to be of high relevance in drug treatment. Even if we know that the drug has an inhibitory effect on the target kinases, we cannot predict without additional knowledge whether missing phosphorylation has an enhancing or decreasing effect on the biological process.
The constitutively active kinaseBCR ABL results in a strong anti apoptotic phenotype. Inhibition counteracts this behavior. Inhibition of LYN has a similar effect in this context. Contrary to this, MAPK14 inhibition rescues cells from apoptosis. Only through the complex interplay of different signals, the malignant cells die upon treatment as desired. Hence, visualization of the network together with its disturbers strongly aids in interpreting their influence. This is a great advantage compared to simple GO enrichment analysis which does not display the relationship of the proteins to each other. The top ranked perturbed functional sub network is based on the epidermal growth factor receptor signaling pathway. It is peripherally interacting with six kinases of the drug profile.
Three additional kinases are directly interacting with EGFR but also interfering with 7 further proteins of the signaling cascade. Additionally, the crosstalk between the pulled down nonkinase members and the functional network is very high. In total 13 out of 33 EGFR signaling components are interacting with the drug profile. EGFR is not expressed in hematopoietic cells but this sub network strongly suggests that bafetinib has the potential to interfere with EGFR signaling for instance in lung cancer cells. Recently, it was shown through the combination of chemical proteomics, phosphoproteomics and functional genomics that dasatinib, a broad spectrum kinase inhibitor, leads to apoptosis in lung cancer cells via inhibition of SRC, EGFR, FYN and, notably, LYN. Therefore, it is possible that also bafetinib might have a pro apoptotic effect on these cells as it is also a potent inhibitor of LYN. While expression of dasatinib insensitive g