The KidsCancerKinome: Validation of Cell Cycle Genes as Potential Drug Targets in Pediatric Tumors
The KCK consortium has validated CDK2 as potential drug target in six highly malignant pediatric tumor types (i.e Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and ALL). The stepwise procedure started with the selection of genes that can be targeted using small molecule inhibitors. Drug target genes and signal transduction routes were studied using Affymetrix mRNA profiles of over 500 tumors and cell lines. Cell cycle regulating signal transduction genes showed expression patterns that were significantly different from reference tissues and expression was related to poor prognosis. The next step to evaluate the potential drug targets consisted of targeted knockdown using RNA interference. Inhibition of CDK2 resulted in significant phenotypes in several pediatric tumor models. Cell lines from most tumor types showed growth inhibition and differentiation. Neuroblastoma cell lines showed extensive apoptosis. Highly interesting was the synthetic lethal relation between CDK2 and the driving oncogene MYCN. These findings warranted further evaluation using the CDK2 inhibiting small molecules. Roscovitine was tested in the core panel of pediatric tumor cell lines and more extensive in tumor types that showed high sensitivity for the compound. Neuroblastoma cell lines were most sensitive with IC50 in the low uM range. CDK inhibiting small molecules are now being evaluated in in vivo mouse xenograft models.