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.

INKA, an integrative data analysis pipeline for phosphoproteomic inference of active kinases

VURCHIO, VALENTINA;Bertotti A.;Trusolino L.;
2019-01-01

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.
2019
15
4
1
22
https://onlinelibrary.wiley.com/journal/17444292
cancer; computational tool; drug selection; kinase–substrate phosphorylation network; single-sample analysis
Beekhof R.; van Alphen C.; Henneman A.A.; Knol J.C.; Pham T.V.; Rolfs F.; Labots M.; Henneberry E.; Le Large T.Y.S.; de Haas R.R.; Piersma S.R.; Vurchio V.; Bertotti A.; Trusolino L.; Verheul H.M.W.; Jimenez C.R.
File in questo prodotto:
File Dimensione Formato  
msb.20188250.pdf

Accesso aperto

Descrizione: Articolo principale
Tipo di file: PDF EDITORIALE
Dimensione 2.15 MB
Formato Adobe PDF
2.15 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1713251
Citazioni
  • ???jsp.display-item.citation.pmc??? 17
  • Scopus 41
  • ???jsp.display-item.citation.isi??? 42
social impact