biostudies-literatureMalone CFNational Cancer Institute (NCI)Friends For LifeNational Cancer InstituteNCI NIH HHSThe Pussycat Foundation285-300https://www.ebi.ac.uk/biostudies/studies/S-EPMC9938728biostudies-literatureUnknown83(2)Aberrant RAS/MAPK signaling is a common driver of oncogenesis that can be therapeutically targeted with clinically approved MEK inhibitors. Disease progression on single-agent MEK inhibitors is common, however, and combination therapies are typically required to achieve significant clinical benefit in advanced cancers. Here we focused on identifying MEK inhibitor-based combination therapies in neuroblastoma with mutations that activate the RAS/MAPK signaling pathway, which are rare at diagnosis but frequent in relapsed neuroblastoma. A genome-scale CRISPR-Cas9 functional genomic screen was deployed to identify genes that when knocked out sensitize RAS-mutant neuroblastoma to MEK inhibition. Loss of either CCNC or CDK8, two members of the mediator kinase module, sensitized neuroblastoma to Cancer researchTranscriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors.PMC9938728P01 CA217959F32 CA2432661P01 CA217959R35 CA210030Thayakumar AStegmaier KGoodale AAlexe GKim MEngel KKhalid DGray NSHatcher JMForman ABMalone CFRobichaud AConway ASMeyer APiccioni FfalseTranscriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors.Aberrant RAS/MAPK signaling is a common driver of oncogenesis that can be therapeutically targeted with clinically approved MEK inhibitors. Disease progression on single-agent MEK inhibitors is common, however, and combination therapies are typically required to achieve significant clinical benefit in advanced cancers. Here we focused on identifying MEK inhibitor-based combination therapies in neuroblastoma with mutations that activate the RAS/MAPK signaling pathway, which are rare at diagnosis but frequent in relapsed neuroblastoma. A genome-scale CRISPR-Cas9 functional genomic screen was deployed to identify genes that when knocked out sensitize RAS-mutant neuroblastoma to MEK inhibition. Loss of either CCNC or CDK8, two members of the mediator kinase module, sensitized neuroblastoma to 2023-01-01T00:00:00Z2023 Jan2026-05-29T00:27:26.278Z2025-04-06T16:24:19.954ZS-EPMC99387283639896510.1158/0008-5472.CAN-21-430910.1158/0008-5472.can-21-4309