Abstract PD1-12: Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib

Abstract

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 adverse effects 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 use molecular and functional profiling by mRNA sequencing, mass spectrometry-based proteomics, and GR-based dose-response assays to obtain complementary views of the mechanisms of action of CDK4/6 inhibitors. We show that abemaciclib, but not ribociclib or palbociclib, is a potent inhibitor of kinases other than CDK4/6, including CDK1/Cyclin B, which appears to cause arrest in the G2 phase of the cell cycle, and CDK2/Cyclin E/A, which is implicated in resistance to palbociclib. We show that inhibition of these additional targets is accessible in a xenograft model. Whereas ribociclib and palbociclib induce cytostasis, and cells adapt to these drugs within 2-3 days of exposure, abemaciclib induces cell death and durably blocks cell proliferation. Abemaciclib is active even in retinoblastoma protein (pRb)-deficient cells in which CDK4/6 inhibition by palbociclib or ribociclib is completely ineffective. The degree of polypharmacology of small molecule drugs is increasingly viewed as an important consideration in their design, with implications for efficacy, toxicity, and acquired resistance. In the case of CDK4/6 inhibitors, we propose that abemaciclib polypharmacology elicits unique molecular responses. More generally, we propose that multi-omic approaches are required to fully elucidate the spectrum of targets relevant to drug action in tumor cells. We expect such understanding to assist in stratifying patient populations and ordering sequential therapies when resistance arises. Citation Format: Mills CE, Hafner M, Subramanian K, Chen C, Chung M, Boswell SA, Everley RA, Walmsley CS, Juric D, Sorger PK. Omics profiling of CDK4/6 inhibitors reveals functionally important secondary targets of abemaciclib [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-12.