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

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.