Multiomics Profiling Establishes the Polypharmacology of FDA-Approved CDK4/6 Inhibitors and the Potential for Differential Clinical Activity
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Abstract
The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five different phenotypic and biochemical assays to compare approved inhibitors of cyclin-dependent kinases 4/6-collectively regarded as breakthroughs in the treatment of hormone receptor-positive breast cancer. We find that transcriptional, proteomic, and phenotypic changes induced by palbociclib, ribociclib, and abemaciclib differ significantly; abemaciclib in particular has advantageous activities partially overlapping those of alvocidib, an older polyselective CDK inhibitor. In cells and mice, abemaciclib inhibits kinases other than CDK4/6 including CDK2/cyclin A/E-implicated in resistance to CDK4/6 inhibition-and CDK1/cyclin B. The multifaceted experimental and computational approaches described here therefore uncover underappreciated differences in CDK4/6 inhibitor activities with potential importance in treating human patients.
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Cites
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- Authors
- Hafner, M., Mills, C. E., Subramanian, K., Chen, C., Chung, M., Boswell, S. A., Everley, R. A., Liu, C., Walmsley, C. S., Juric, D., & Sorger, P. K.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Juric, Dejan
- Sorger, Peter K.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 26
- Issue
- 8
- Pages
- 1067-1080.e8
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC6936329
- OpenAlex
- W2923271724
- Cited by
- 250
- References
- 12
- Citations by year
- 2026: 25 · 2025: 43 · 2024: 37 · 2023: 44 · 2022: 37 · 2021: 34 · 2020: 27 · 2019: 3
- FWCI
- 19.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50-GM107618, U54-CA225088, U54-HL127365)
- Pfizer
- Genentech
- EMD Serono
- Sächsische Aufbaubank
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- CDK4/6 inhibitors, polypharmacology, abemaciclib, palbociclib, ribociclib, flavopiridol, hormone receptor-positive breast cancer, off-target kinase inhibition, CDK2, CDK1, multi-omics profiling, drug resistance
- MeSH terms
- Animals, Female, Humans, Mice, Nude, United States, United States Food and Drug Administration, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, Polypharmacology
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