TY - JOUR
T1 - Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma
AU - Dolman, M. Emmy M.
AU - Poon, Evon
AU - Ebus, Marli E.
AU - Den Hartog, Ilona J.M.
AU - Van Noesel, Carel J.M.
AU - Jamin, Yann
AU - Hallsworth, Albert
AU - Robinson, Simon P.
AU - Petrie, Kevin
AU - Sparidans, Rolf W.
AU - Kok, Robbert J.
AU - Versteeg, Rogier
AU - Caron, Huib N.
AU - Chesler, Louis
AU - Molenaar, Jan J.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/11/15
Y1 - 2015/11/15
N2 - PURPOSE: MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519.EXPERIMENTAL DESIGN: Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma.RESULTS: AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug.CONCLUSIONS: This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification.
AB - PURPOSE: MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519.EXPERIMENTAL DESIGN: Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma.RESULTS: AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug.CONCLUSIONS: This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification.
KW - Animals
KW - Apoptosis/drug effects
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Cyclin-Dependent Kinase 2/biosynthesis
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Mice
KW - N-Myc Proto-Oncogene Protein
KW - Neuroblastoma/drug therapy
KW - Nuclear Proteins/biosynthesis
KW - Oncogene Proteins/biosynthesis
KW - Piperidines/administration & dosage
KW - Protein Kinase Inhibitors/administration & dosage
KW - Pyrazoles/administration & dosage
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=84943642374&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-0313
DO - 10.1158/1078-0432.CCR-15-0313
M3 - Article
C2 - 26202950
AN - SCOPUS:84943642374
VL - 21
SP - 5100
EP - 5109
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 22
ER -