dinaciclib and Neuroblastoma

Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-sequencing data from 498 patients with neuroblastoma and revealed a differentially overexpressed gene signature in MYCN nonamplified neuroblastomas with telomerase reverse transcriptase (

Topics: Adolescent; Animals; Antineoplastic Agents; Bone Marrow; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Proteins; Cell Line, Tumor; Child, Preschool; Chromatin; Chromatin Immunoprecipitation Sequencing; Cyclic N-Oxides; Cyclin-Dependent Kinases; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 2-Ring; Histones; Humans; Indolizines; Mice; Neuroblastoma; Piperazines; Promoter Regions, Genetic; Pyrazoles; Pyridazines; Pyridinium Compounds; Signal Transduction; Telomerase; Transcription Factors; Transcriptome; Up-Regulation; Xenograft Model Antitumor Assays

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is responsible for approximately 15% of cancer-related mortality in children. Aberrant activation of cyclin-dependent kinases (CDKs) has been shown to contribute to tumor cell progression in many cancers including NB. Therefore, small molecule inhibitors of CDKs comprise a strategic option in cancer therapy. Here we show that a novel multiple-CDK inhibitor, dinaciclib (SCH727965, MK-7965), exhibits potent anti-proliferative effects on a panel of NB cell lines by blocking the activity of CDK2 and CDK9. Dinaciclib also significantly sensitized NB cell lines to the treatment of chemotherapeutic agents such as doxorubicin (Dox) and etoposide (VP-16). Furthermore, dinaciclib revealed in vivo antitumor efficacy in an orthotopic xenograft mouse model of two NB cell lines and blocked tumor development in the TH-MYCN transgenic NB mouse model. Taken together, this study suggests that CDK2 and CDK9 are potential therapeutic targets in NB and that abrogating CDK2 and CDK9 activity by small molecules like dinaciclib is a promising strategy and a treatment option for NB patients.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cyclic N-Oxides; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 9; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Humans; Indolizines; Mice; Neuroblastoma; Phosphorylation; Protein Kinase Inhibitors; Pyridinium Compounds; Signal Transduction; Xenograft Model Antitumor Assays