Molecular Systems Biology | |
INKA, an integrative data analysis pipeline for phosphoproteomic inference of active kinases | |
Andrea Bertotti1  Valentina Vurchio1  Livio Trusolino1  Mariette Labots2  Henk MW Verheul2  Connie R Jimenez2  Robin Beekhof2  Jaco C Knol2  Tessa YS Le Large2  Alex A Henneman2  Frank Rolfs2  Carolien vanAlphen2  Richard R deHaas2  Sander R Piersma2  Thang V Pham2  Evan Henneberry3  | |
[1] Department of Oncology Candiolo Cancer Institute IRCCS University of Torino Torino Italy;Medical Oncology Cancer Center Amsterdam Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands;OncoProteomics Laboratory Cancer Center Amsterdam Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands; | |
关键词: cancer; computational tool; drug selection; kinase–substrate phosphorylation network; single‐sample analysis; | |
DOI : 10.15252/msb.20188250 | |
来源: DOAJ |
【 摘 要 】
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.
【 授权许可】
Unknown