Abstract B60: Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib

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. In vitro profiling of the CDK4/6 inhibitors has shown abemaciclib to be more potent on target, but less selective than either palbociclib or ribociclib. We sought to systematically investigate the functional consequences of abemaciclib’s polypharmacology. We used molecular and phenotypic profiling by mRNA sequencing, mass spectrometry-based proteomics, and GR-based dose-response assays to characterize the mechanisms of action of the three CDK4/6 inhibitors. Inhibition of CDKs other than CDK4/6 by abemaciclib resulted in an arrest in the G2 phase of the cell cycle, a prolonged inhibition of growth, and cytotoxicity, even in retinoblastoma protein (pRb)-deficient cells. Abemaciclib elicited unique molecular responses at clinically achievable concentrations that are likely to be therapeutically advantageous and prevented cross-resistance with ribociclib and palbociclib. More generally, 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 assist in stratifying patient populations and in ordering sequential therapies when resistance arises. Citation Format: Caitlin E. Mills, Marc Hafner, Kartik Subramanian, Chen Chen, Sarah A. Boswell, Robert A. Everley, Dejan Juric, Peter K. Sorger. Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B60.