GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE303nnn/GSE303026/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303026GEOGSEfalseCDK8/19 inhibition suppresses adaptive resistance to CDK4/6 inhibitors in vitro and in vivoCDK4/6 inhibitors have become a standard of care for estrogen receptor-positive breast cancer and are being developed for other malignancies. However, resistance to these drugs readily develops, limiting their impact on patient survival. Mechanisms of resistance to CDK4/6 inhibition involve multiple changes in gene expression, which may be followed by genetic alterations. We have investigated the process of tumor cell adaptation to CDK4/6 inhibitors and the impact of selective inhibitors of CDK8/19 Mediator kinases, broad-spectrum regulators of transcriptional reprogramming, on such adaptation. The addition of CDK8/19 inhibitors (SNX631/SNX631-6) prevented the development of CDK4/6 inhibitor resistance in different cell lines and in vivo tumor models with varying levels of CDK4/6 inhibitor sensitivity. RNA-seq analysis revealed specific transcriptomic changes associated with adaptation to palbociclib in vitro and in vitro. Combining palbociclib with CDK8/19 inhibitors suppressed many of the adaptation-associated changes in gene expression. The findings indicate a potential therapeutic benefit of combining CDK4/6 and CDK8/19 inhibitors.2026/07/24GSE303026GSM9116058GSM9116079GSM9116057GSM9116059GSM9116076GSM9116054GSM9116075GSM9116053GSM9116078GSM9116056GSM9116055GSM9116077GSM9116072GSM9116050GSM9116071GSM9116052GSM9116074GSM9116073GSM9116051GSM9116070GSM9116047GSM9116069GSM9116068GSM9116046GSM9116049GSM9116048GSM9116065GSM9116043GSM9116064GSM9116086GSM9116067GSM9116045GSM9116044GSM9116066GSM9116061GSM9116083GSM9116060GSM9116082GSM9116063GSM9116085GSM9116084GSM9116062GSM9116081GSM9116080207951857334281303026Homo sapiens