Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells
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 th...
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Nature Portfolio
2021-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-84082-3 |
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| author | Marta Buzzetti Sonia Morlando Dimitrios Solomos Ammara Mehmood Alexander W. I. Cox Mattia Chiesa Yuri D’Alessandra Michela Garofalo Caroline H. Topham Gianpiero Di Leva |
| author_facet | Marta Buzzetti Sonia Morlando Dimitrios Solomos Ammara Mehmood Alexander W. I. Cox Mattia Chiesa Yuri D’Alessandra Michela Garofalo Caroline H. Topham Gianpiero Di Leva |
| author_sort | Marta Buzzetti |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5a64e631106b44d6a6c20f70baf716a7 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2021-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-5a64e631106b44d6a6c20f70baf716a72025-02-09T12:38:29ZengNature PortfolioScientific Reports2045-23222021-03-0111111610.1038/s41598-021-84082-3Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cellsMarta Buzzetti0Sonia Morlando1Dimitrios Solomos2Ammara Mehmood3Alexander W. I. Cox4Mattia Chiesa5Yuri D’Alessandra6Michela Garofalo7Caroline H. Topham8Gianpiero Di Leva9School of Science, Engineering and Environment, Biomedical Research CentreSchool of Science, Engineering and Environment, Biomedical Research CentreSchool of Science, Engineering and Environment, Biomedical Research CentreSchool of Science, Engineering and Environment, Biomedical Research CentreCancer Research UK Lung Cancer Centre of Excellence, at Manchester and University College LondonBioinformatics and Artificial Intelligence Facility, Centro Cardiologico Monzino IRCCSImmunology and Functional Genomics Unit, Centro Cardiologico Monzino IRCCSTranscriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of ManchesterSchool of Science, Engineering and Environment, Biomedical Research CentreSchool of Pharmacy and Bioengineering, Guy Hilton Research Centre, Keele UniversityAbstract 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.https://doi.org/10.1038/s41598-021-84082-3 |
| spellingShingle | Marta Buzzetti Sonia Morlando Dimitrios Solomos Ammara Mehmood Alexander W. I. Cox Mattia Chiesa Yuri D’Alessandra Michela Garofalo Caroline H. Topham Gianpiero Di Leva Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells Scientific Reports |
| title | Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells |
| title_full | Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells |
| title_fullStr | Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells |
| title_full_unstemmed | Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells |
| title_short | Pre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells |
| title_sort | pre therapeutic efficacy of the cdk inhibitor dinaciclib in medulloblastoma cells |
| url | https://doi.org/10.1038/s41598-021-84082-3 |
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