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

Cyclin-dependent kinase 4/6 (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. We 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 adaptations. Adaptive non-genetic resistance to CDK4/6 inhibitors develops rapidly, but the addition of CDK8/19 inhibitors prevents the development of this resistance in different tumor models, in vitro and in vivo. RNA sequencing (RNA-seq) analysis reveals that combining CDK4/6 and CDK8/19 inhibitors suppresses many of the adaptation-associated changes in gene expression, including those previously associated with CDK4/6 inhibitor resistance. The findings suggest that CDK8/19 inhibition may greatly extend the therapeutic benefit of CDK4/6 inhibitors.