Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes beta TrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1 epsilon not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1 epsilon and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1 epsilon as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors. Acquisition of CDK4/6i resistance represents a major clinical challenge. Here, the authors report that inhibition of CK1 epsilon can prevent acquisition of CDK4/6i resistance, potentiating the therapeutic efficacy of CDK4/6i in human breast cancer.

Automated summary

Inhibition of CK1 epsilon can prevent acquisition of CDK4/6i resistance, enhancing the therapeutic efficacy of CDK4/6i in human breast cancer.