Therapeutically advantageous secondary targets of abemaciclib identified by multi-omics profiling of CDK4/6 inhibitors

Abstract

FDA approval of multiple drugs differing in chemical structures but targeting the same protein raises the question whether such drugs have sufficiently similar mechanisms of action to be considered functionally equivalent. In this paper we compare three recently approved inhibitors of the cyclin-dependent kinases CDK4/6 - palbociclib, ribociclib, and abemaciclib - that are becoming important therapies for the treatment of hormone-receptor positive breast and potentially other cancers. We find that transcriptional and proteomic changes induced by the three drugs differ significantly and that abemaciclib has unique cellular activities including induction of cell death (even in pRb-deficient cells), arrest in the G2 phase of the cell cycle, and reduced drug adaptation. These activities appear to arise from inhibition of kinases other than CDK4/6 including CDK2/Cyclin A/E and CDK1/Cyclin B.\n\nSIGNIFICANCEThe target profiles of most drugs are established relatively early in their development and are not systematically revisited at the time of approval. Scattered reports suggest that palbociclib, ribociclib, and abemaciclib differ in pharmacokinetics, dosing, and adverse effects but the three drugs are generally regarded as similar. Our finding that the drugs differ substantially in mechanism of action - abemaciclib retains activities of the earlier-generation drug alvocidib - suggests the potential for different uses in the clinic: in particular, abemaciclib may show activity in patients progressing on palbociclib or ribociclib. More generally, our approach relying on data from five distinct phenotypic and biochemical assays strongly suggests that a multi-faceted approach is necessary to get a reliable picture the target spectrum of kinase inhibitors.