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Kinase-Substrate Enrichment Analysis Provides Insights into the Heterogeneity of Signaling Pathway Activation in Leukemia Cells

Sci. Signal.  26 Mar 2013:
Vol. 6, Issue 268, pp. rs6
DOI: 10.1126/scisignal.2003573

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Therapeutic Targeting with Phosphoproteomics

Because oncogenic mutations frequently occur in genes encoding kinases, kinase inhibitors are often used as cancer therapeutics. However, because of the complexity of kinase signaling networks and the heterogeneous nature of oncogenic mutations, it is difficult to predict how cancer cells will respond to a given kinase inhibitor. Casado et al. performed phosphoproteomic analysis of human acute myeloid leukemia (AML) cell lines and used a computational approach of “signal averaging” to reduce the noise in the phosphoproteomics data, thus monitoring global kinase activation patterns as well as the effects of select inhibitors. In addition to identifying kinase networks associated with AML, this approach accurately predicted the relative sensitivities of patient-derived AML cells to inhibitors. Such profiling of kinase networks could be applied to stratify cancers based on their predicted responses to kinase inhibition.