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    Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells

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    Authors
    Buzzetti, Marta
    Morlando, S.
    Solomos, D.
    Mehmood, A.
    Cox, A. W. I.
    Chiesa, M.
    D'Alessandra, Y.
    Garofalo, Michela
    Topham, C. H.
    Di Leva, G.
    Affiliation
    School of Science, Engineering and Environment, Biomedical Research Centre, Salford, Greater Manchester, UK.
    Issue Date
    2021
    
    Metadata
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    Abstract
    Medulloblastoma (MB) is the most common aggressive paediatric brain tumour and, despite the recent progress in the treatments of MB patients, there is still an urgent need of complementary or alternative therapeutic options for MB infants. Cyclin Dependent Kinase inhibitors (CDKi) are at the front-line of novel targeted treatments for multiple cancers and the CDK4/6 specific inhibitor palbociclib has been pre-clinically identified as an effective option for MB cells. Herein, we identified the pan-CDKi dinaciclib as a promising alternative to palbociclib for the suppression of MB cells proliferation. We present evidence supporting dinaciclib's ability to inhibit MB cells in vitro proliferation at considerably lower doses than palbociclib. Sequencing data and pathway analysis suggested that dinaciclib is a potent cell death inducer in MB cells. We found that dinaciclib-triggered apoptosis is triggered by CDK9 inhibition and the resultant reduction in RNA pol II phosphorylation, which leads to the downregulation of the oncogenic marker MYC, and the anti-apoptotic protein MCL-1. Specifically, we demonstrated that MCL-1 is a key apoptotic mediator for MB cells and co-treatment of dinaciclib with BH3 mimetics boosts the therapeutic efficacy of dinaciclib. Together, these findings highlight the potential of multi-CDK inhibition by dinaciclib as an alternative option to CDK4/6 specific inhibition, frequently associated with drug resistance in patients.
    Citation
    Buzzetti M, Morlando S, Solomos D, Mehmood A, Cox AWI, Chiesa M, et al. Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells. Sci Rep. 2021;11(1):5374.
    Journal
    Science Reports
    URI
    http://hdl.handle.net/10541/623853
    DOI
    10.1038/s41598-021-84082-3
    PubMed ID
    33686114
    Additional Links
    https://dx.doi.org/10.1038/s41598-021-84082-3
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41598-021-84082-3
    Scopus Count
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    All Paterson Institute for Cancer Research

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