Refereed journal article or data article (A1)

Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells




List of Authors: Denisova Oxana V, Merisaari Joni, Kaur Amanpreet, Yetukuri Laxman, Jumppanen Mikael, Von Schantz-Fant Carina, Ohlmeyer Michael, Wennerberg Krister, Aittokallio Tero, Taipale Mikko, Westermarck Jukka

Publisher: NATURE PORTFOLIO

Publication year: 2022

Journal: Scientific Reports

Journal name in source: SCIENTIFIC REPORTS

Journal acronym: SCI REP-UK

Volume number: 12

Number of pages: 9

ISSN: 2045-2322

eISSN: 2045-2322

DOI: http://dx.doi.org/10.1038/s41598-022-18118-7

URL: https://doi.org/10.1038/s41598-022-18118-7

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/176327794


Abstract
Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinases and thereby potentially overcome kinase inhibitor resistance. However, in most cases the identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an actionable targets of multi-kinase inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis, and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results, we propose that the application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of the target specificity of multi-kinase inhibitors.

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Last updated on 2022-19-09 at 12:34