title: Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Authors' Affiliations: Division of Oncology and Center for Childhood Cancer Research; Division of Pathology, Children's Hospital of Philadelphia; Department of Pediatrics; Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Julieann
authors.initials: J
authors.lastname: Rader
authors.forename: Mike R
authors.initials: MR
authors.lastname: Russell
authors.forename: Lori S
authors.initials: LS
authors.lastname: Hart
authors.forename: Michael S
authors.initials: MS
authors.lastname: Nakazawa
authors.forename: Lili T
authors.initials: LT
authors.lastname: Belcastro
authors.forename: Daniel
authors.initials: D
authors.lastname: Martinez
authors.forename: Yimei
authors.initials: Y
authors.lastname: Li
authors.forename: Erica L
authors.initials: EL
authors.lastname: Carpenter
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.forename: Sudha
authors.initials: S
authors.lastname: Parasuraman
authors.forename: Giordano
authors.initials: G
authors.lastname: Caponigro
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schnepp
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Wood
authors.forename: Bruce
authors.initials: B
authors.lastname: Pawel
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Cole
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D002648:Child; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D000071447:N-Myc Proto-Oncogene Protein; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D000631:Aminopyridines; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C000589651:ribociclib
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