Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib (Conference Presentation)

The recent introduction of small molecule inhibitors of cyclin-dependent kinases (CDK) 4/6 to the clinic has improved the treatment of hormone receptor positive breast cancer, and shown promise in other malignancies. The three clinically-used CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are reported to be broadly similar although recent data suggest that abemaciclib has distinct single-agent activity in patients and a unique toxicity profile. Key questions are: How do these drugs differ at the molecular level? Should such differences inform their use in the clinic? Can these three agents be used interchangeably or should patient stratification differ between them? We started to address these questions by characterizing the spectrum of kinases inhibited by palbociclib, ribociclib, and abemaciclib, and the functional consequences of their inhibition in cell lines using multiple methods. First, in vitro biochemical profiling of the CDK4/6 inhibitors confirmed abemaciclib to be more potent on target, but less selective than either palbociclib or ribociclib. We used profiling by mRNA sequencing to capture differences in transcriptional response; mass spectrometry-based proteomics to infer changes in kinase activity following treatment, and imaging-based dose response, and immunofluorescence assays to characterize the phenotypic responses of breast cancer cell lines to the three CDK4/6 inhibitors. We propose that multi-omic approaches are required to fully elucidate the spectrum of targets relevant to drug mechanisms of action in cells, and we expect such understanding to inform clinical use of these drugs.