Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma

Clin Cancer Res. 2013 Nov 15;19(22):6173-82. doi: 10.1158/1078-0432.CCR-13-1675. Epub 2013 Sep 17.

Abstract

Purpose: Neuroblastoma is a pediatric cancer that continues to exact significant morbidity and mortality. Recently, a number of cell-cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes.

Experimental procedures: We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011 (Novartis Oncology), a highly specific CDK4/6 inhibitor.

Results: Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nmol/L in sensitive lines). LEE011 caused cell-cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. Although our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (P = 0.01), the identification of additional clinically accessible biomarkers is of high importance.

Conclusions: Taken together, our data show that LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease. Clin Cancer Res; 19(22); 6173-82. ©2013 AACR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminopyridines / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Child
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / genetics
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Mice
  • Mice, SCID
  • N-Myc Proto-Oncogene Protein
  • Neoplasm Transplantation
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / genetics
  • Nuclear Proteins / genetics
  • Oncogene Proteins / genetics
  • Phosphorylation / drug effects
  • Polymorphism, Single Nucleotide
  • Protein Kinase Inhibitors / therapeutic use*
  • Purines / pharmacology*
  • RNA Interference
  • RNA, Small Interfering
  • Retinoblastoma Protein / metabolism
  • Signal Transduction / drug effects
  • Transplantation, Heterologous

Substances

  • Aminopyridines
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Protein Kinase Inhibitors
  • Purines
  • RNA, Small Interfering
  • Retinoblastoma Protein
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • ribociclib