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Mol Syst Biol ; 15(4): e8250, 2019 04 12.
Article in English | MEDLINE | ID: mdl-30979792

ABSTRACT

Identifying hyperactive kinases in cancer is crucial for individualized treatment with specific inhibitors. Kinase activity can be discerned from global protein phosphorylation profiles obtained with mass spectrometry-based phosphoproteomics. A major challenge is to relate such profiles to specific hyperactive kinases fueling growth/progression of individual tumors. Hitherto, the focus has been on phosphorylation of either kinases or their substrates. Here, we combined label-free kinase-centric and substrate-centric information in an Integrative Inferred Kinase Activity (INKA) analysis. This multipronged, stringent analysis enables ranking of kinase activity and visualization of kinase-substrate networks in a single biological sample. To demonstrate utility, we analyzed (i) cancer cell lines with known oncogenes, (ii) cell lines in a differential setting (wild-type versus mutant, +/- drug), (iii) pre- and on-treatment tumor needle biopsies, (iv) cancer cell panel with available drug sensitivity data, and (v) patient-derived tumor xenografts with INKA-guided drug selection and testing. These analyses show superior performance of INKA over its components and substrate-based single-sample tool KARP, and underscore target potential of high-ranking kinases, encouraging further exploration of INKA's functional and clinical value.


Subject(s)
Neoplasms/enzymology , Phosphotransferases/analysis , Proteomics/methods , Systems Biology/methods , Cell Line, Tumor , Enzyme Activation , Humans , K562 Cells , Mass Spectrometry , Phosphoproteins/analysis
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