Transcriptomics,Multiomics

Dataset Information

6

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells


ABSTRACT: Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. CDK2 shRNA in a tet repressor system was stably transfected in the IMR32 cell line. Time course analysis was performed in triplicate after induction of CDK2 shRNA at 5 time points.

OTHER RELATED OMICS DATASETS IN: PRJNA115193PRJNA122895

ORGANISM(S): Homo sapiens  

SUBMITTER: Jan Molenaar   Jan Koster  Rogier Versteeg 

PROVIDER: E-GEOD-16480 | ArrayExpress | 2014-05-19

SECONDARY ACCESSION(S): GSE16480PRJNA122895

REPOSITORIES: GEO, ArrayExpress

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E-GEOD-16480.idf.txt Idf
E-GEOD-16480.processed.1.zip Processed
E-GEOD-16480.raw.1.zip Raw
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Publications

Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells.

Molenaar Jan J JJ   Ebus Marli E ME   Geerts Dirk D   Koster Jan J   Lamers Fieke F   Valentijn Linda J LJ   Westerhout Ellen M EM   Versteeg Rogier R   Caron Huib N HN  

Proceedings of the National Academy of Sciences of the United States of America 20090612 31


Two genes have a synthetically lethal relationship when the silencing or inhibiting of 1 gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetically lethal to neuroblastoma cells with MYCN ampli  ...[more]

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