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

• Published in: Scientific reports 2021-03, Vol.11 (1), p.5374-5374, Article 5374
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 692/4017; 692/4028/67; Apoptosis; Brain cancer; Brain tumors; Cancer therapies; Cell cycle; Cell death; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cyclic N-Oxides - pharmacology; Cyclin-dependent kinase; Cyclin-dependent kinase 4; Cyclin-dependent kinases; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - metabolism; DNA methylation; DNA-directed RNA polymerase; Drug dosages; Drug resistance; Drug Screening Assays, Antitumor; Gene expression; Genomics; Humanities and Social Sciences; Humans; Indolizines - pharmacology; Infants; Kinases; Lung cancer; Mcl-1 protein; Medical prognosis; Medical research; Medulloblastoma; Medulloblastoma - drug therapy; Medulloblastoma - enzymology; Medulloblastoma - pathology; multidisciplinary; Myc protein; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Patients; Pediatrics; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Pyridinium Compounds - pharmacology; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-84082-3

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.