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

Buzzetti, Marta; Morlando, Sonia; Solomos, Dimitrios; Mehmood, Ammara; Cox, Alexander W.I.; Chiesa, Mattia; D’Alessandra, Yuri; Garofalo, Michela; Topham, Caroline H.; Di Leva, Gianpiero

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Authors

Marta Buzzetti

Sonia Morlando

Dimitrios Solomos

Ammara Mehmood

Alexander W.I. Cox

Mattia Chiesa

Yuri D’Alessandra

Michela Garofalo

Caroline H. Topham



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-induced 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, A. W., Chiesa, M., …Di Leva, G. (2021). Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells. Scientific reports, 11, Article 5374. https://doi.org/10.1038/s41598-021-84082-3

Journal Article Type Article
Acceptance Date Feb 5, 2021
Publication Date Mar 8, 2021
Publicly Available Date Jun 29, 2023
Journal Scientific Reports
Print ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 11
Article Number 5374
DOI https://doi.org/10.1038/s41598-021-84082-3
Keywords cancer; molecular medicine
Publisher URL http://doi.org/10.1038/s41598-021-84082-3

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