Tracking CDK1 Dynamics With a Novel Biosensor Mouse and Clinical Cohorts to Predict CDK4/6 Inhibitor Sensitivity in ER+ Breast Cancer

ABSTRACT High‐risk estrogen receptor positive (ER+) early breast cancer (EBC) is managed with endocrine therapies and cyclin‐dependent kinase (CDK) 4/6 inhibitors, although no standard molecular markers clinically identify these tumors. CDK1 lies immediately downstream of CDK4/6 but has not been investigated as a prognostic marker for ER+ disease. Here, we integrate real‐time imaging of a novel Cdk1 activity biosensor mouse with clinical cohorts to establish CDK1 as a candidate biomarker of progression and therapeutic sensitivity. Using the MMTV‐PyMT;MMTV‐Cre;Cdk1‐FRET biosensor mouse, we visualized Cdk1 upregulation in situ during the transition to invasive ductal carcinoma (IDC). Clinically, we identified that pCDK1 T161 is specifically upregulated in IDC, and that pCDK1 Y15 is prognostic of poor relapse‐free survival in stage 1 disease. We further characterized CDK1 activity as part of a dynamic adaptive response to CDK4/6 inhibition: the CDK1/cyclin B1 complex was suppressed, then rebounded within 3 days. In the NeoPalAna trial, non‐responders incompletely suppressed CDK1 . Palbociclib‐resistant cells recovered basal CDK1 in vitro, non‐responsive tumors exhibited elevated Cdk1 activity in vivo, and CDK1 was elevated in CDK4/6 inhibitor‐resistant patient tumors. Together, our findings position CDK1 as a candidate biomarker for poor prognosis in early disease, and an indicator of adaptive responses and resistance to CDK4/6 inhibition.