Development of actionable targets of multi-kinase inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells
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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.
|Status||Udgivet - 2022|
We thank the High Throughput Biomedicine Unit at the Institute for Molecular Medicine Finland supported by Biocenter Finland. Taina Kalevo-Mattila is acknowledged for excellent technical support as well as the entire Turku Bioscience personnel for excellent working environment. The authors thank all the colleagues that shared research tools as mentioned in the materials and methods.
Project was funded by Jane and Aatos Erkko Foundation (JW), Finnish Cultural Foundation (00160159, OD), Turku Doctoral Programme of Molecular Medicine (JM) and Academy of Finland (TA).
© 2022, The Author(s).