Therapeutically advantageous secondary targets of abemaciclib identified by multi-omics profiling of CDK4/6 inhibitors
Marc Hafner, Caitlin E. Mills, Kartik Subramanian, Chen Chen, Mirra Chung, Sarah A. Boswell, Robert A. Everley, Charlotte S. Walmsley, Dejan Juric, and Peter K. Sorger
Received: 20th October 17
Three inhibitors of the cyclin-dependent kinases CDK4/6, palbociclib, ribociclib, and abemaciclib, have emerged as highly promising therapies for the treatment of breast cancer and other solid tumors. These drugs are reported to have similar mechanisms of action although recent data suggest that abemaciclib exhibits distinct single-agent activity and toxicity. We compare their mechanisms of action using biochemical assays, mRNA profiling, mass spectrometry-based phospho-proteomics, and GR-based dose-response assays. We find that abemaciclib has activities not shared by palbociclib or ribociclib 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 CDKs other than CDK4/6 including CDK2/Cyclin A/E and CDK1/Cyclin B. We propose that inhibition of these kinases by abemaciclib overcomes known mechanisms of resistance to CDK4/6 inhibition and may be therapeutically advantageous for patients whose tumors progress on palbociclib or ribociclib.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.