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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5a64e631106b44d6a6c20f70baf716a7
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5a64e631106b44d6a6c20f70baf716a7
record_format	dspace
spelling	oai:doaj.org-article:5a64e631106b44d6a6c20f70baf716a72021-12-02T13:30:12ZPre-therapeutic efficacy of the CDK inhibitor dinaciclib in medulloblastoma cells10.1038/s41598-021-84082-32045-2322https://doaj.org/article/5a64e631106b44d6a6c20f70baf716a72021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84082-3https://doaj.org/toc/2045-2322Abstract 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.Marta BuzzettiSonia MorlandoDimitrios SolomosAmmara MehmoodAlexander W. I. CoxMattia ChiesaYuri D’AlessandraMichela GarofaloCaroline H. TophamGianpiero Di LevaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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
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
title	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_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_sort	pre-therapeutic efficacy of the cdk inhibitor dinaciclib in medulloblastoma cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5a64e631106b44d6a6c20f70baf716a7
work_keys_str_mv	AT martabuzzetti pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT soniamorlando pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT dimitriossolomos pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT ammaramehmood pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT alexanderwicox pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT mattiachiesa pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT yuridalessandra pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT michelagarofalo pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT carolinehtopham pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells AT gianpierodileva pretherapeuticefficacyofthecdkinhibitordinaciclibinmedulloblastomacells
_version_	1718392916117815296

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

Ejemplares similares