CDK8/19 inhibition suppresses adaptive resistance to CDK4/6 inhibitors in vitro and in vivo

CDK4/6 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.