Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single-agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggest that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Azepines / administration & dosage*
-
Azepines / pharmacology
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cell Survival / drug effects
-
Cerebellar Neoplasms / drug therapy
-
Cerebellar Neoplasms / genetics*
-
Cyclin-Dependent Kinase 2
-
Drug Synergism
-
Female
-
Humans
-
Medulloblastoma / drug therapy*
-
Medulloblastoma / genetics
-
Piperazines / administration & dosage
-
Piperazines / pharmacology
-
Protein Kinase Inhibitors / administration & dosage*
-
Protein Kinase Inhibitors / pharmacology
-
Protein Stability / drug effects
-
Proto-Oncogene Proteins c-myc / chemistry
-
Proto-Oncogene Proteins c-myc / genetics*
-
Pyrazoles / administration & dosage
-
Pyrazoles / pharmacology
-
Pyridines / administration & dosage
-
Pyridines / pharmacology
-
Quinazolines / administration & dosage
-
Quinazolines / pharmacology
-
Sequence Analysis, RNA
-
Signal Transduction / drug effects
-
Triazoles / administration & dosage*
-
Triazoles / pharmacology
-
Xenograft Model Antitumor Assays
Substances
-
(+)-JQ1 compound
-
Azepines
-
MYC protein, human
-
N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide
-
Piperazines
-
Protein Kinase Inhibitors
-
Proto-Oncogene Proteins c-myc
-
Pyrazoles
-
Pyridines
-
Quinazolines
-
Triazoles
-
CDK2 protein, human
-
Cyclin-Dependent Kinase 2
-
palbociclib