2. Academic Validation
  3. Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells

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

  • Sci Rep. 2022 Aug 13;12(1):13796. doi: 10.1038/s41598-022-18118-7.
Oxana V Denisova 1,  Joni Merisaari 1 2,  Amanpreet Kaur 1,  Laxman Yetukuri 1 3,  Mikael Jumppanen 1,  Carina von Schantz-Fant 3,  Michael Ohlmeyer 4 5,  Krister Wennerberg 3 6,  Tero Aittokallio 3 7 8,  Mikko Taipale 9,  Jukka Westermarck 10 11
Affiliations

Affiliations

  • 1 Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
  • 2 Institute of Biomedicine, University of Turku, Turku, Finland.
  • 3 Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland.
  • 4 Icahn School of Medicine at the Mount Sinai, New York, NY, USA.
  • 5 Atux Iskay LLC, Plainsboro, NJ, USA.
  • 6 Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  • 7 Centre for Biostatistics and Epidemiology, University of Oslo, Oslo, Norway.
  • 8 Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
  • 9 Donnelly Centre, University of Toronto, Toronto, Canada.
  • 10 Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland. jukwes@utu.fi.
  • 11 Institute of Biomedicine, University of Turku, Turku, Finland. jukwes@utu.fi.
PMID: 35963891 DOI: 10.1038/s41598-022-18118-7
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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