Small-molecule inhibitors of CDK4/6 have created new opportunities for the treatment of advanced hormone receptor (HR)-positive breast cancer and show promise in other malignancies.1 Three CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—that have been approved by the FDA for the treatment of HR-positive/HER2-negative breast cancer, 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.2,3 Differences in pharmacokinetics and relative potency for CDK4 versus CDK6 are postulated to account for these differences.
In a presentation at SABCS 2017, the authors used molecular and functional profiling by mRNA sequencing, mass spectrometry–based proteomics, and growth rate (GR)-based dose-response assays to obtain complementary views of the mechanisms of action of CDK4/6 inhibitors.4 They showed 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. Whereas ribociclib and palbociclib induce cytostasis, and cells adapt to these drugs within 2 to 3 days of exposure, abemaciclib induces cell death and durably blocks cell proliferation. Abemaciclib is active (as shown by a decrease in GR value) even in retinoblastoma protein–deficient cells in which CDK4/6 inhibition by palbociclib or ribociclib is 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, the authors proposed that abemaciclib’s polypharmacology elicits unique molecular responses that are likely to be therapeutically advantageous. More generally, they proposed that multi-omic approaches are required to fully elucidate the spectrum of targets relevant to drug action in tumor cells, and that such understanding may assist in stratifying patient populations and sequencing therapies when resistance arises.
- Zardavas D, et al. Expert Opin Investig Drugs. 2017;26:1357-1372.
- Torres-Guzmán R, et al. Oncotarget. 2017;8:69493-69507.
- Goetz MP, et al. J Clin Oncol. 2017;35:3638-3646.
- Hafner M, et al. SABCS 2017. Abstract PD4-02.