Abstract 4432: Multi-omics profiling establishes the polypharmacology of FDA Approved CDK4/6 inhibitors and its impact on drug response
| Autor: | Caitlin E. Mills, Marc A. Hafner, Kartik Subramanian, Chen Chen, Mirra Chung, Sarah A. Boswell, Robert A. Everley, Changchang Liu, Charlotte S. Walmsley, Dejan Juric, Peter K. Sorger |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Cancer Research. 79:4432-4432 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2019-4432 |
| Popis: | FDA approval of multiple drugs with different chemical structures against the same protein target raises the question whether such drugs have sufficiently similar mechanisms of action to be considered functionally equivalent. We compare three recently approved inhibitors of the cyclin-dependent kinases CDK4/6 - palbociclib, ribociclib, and abemaciclib - that have become highly promising therapies for the treatment of breast cancer and potentially other solid tumors. All three drugs have the same nominal targets but differ in selectivity. In humans, abemaciclib uniquely appears to exhibit single-agent activity and has a distinct toxicity profile. We systematically profile targets and activities of these CDK4/6 inhibitors using biochemical assays, mRNA profiling, mass spectrometry-based phospho-proteomics, GR-based dose-response assays, and mouse xenografts. We find that the three drugs differ at a cellular level and that abemaciclib has targets and 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, reduced drug adaptation, and unique transcriptional effects in vitro and in vivo. 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 target known mechanisms of resistance to CDK4/6 inhibition and thus elicit a response in cell lines that are resistant to palbociclib or ribociclib. Citation Format: Caitlin E. Mills, Marc A. Hafner, Kartik Subramanian, Chen Chen, Mirra Chung, Sarah A. Boswell, Robert A. Everley, Changchang Liu, Charlotte S. Walmsley, Dejan Juric, Peter K. Sorger. Multi-omics profiling establishes the polypharmacology of FDA Approved CDK4/6 inhibitors and its impact on drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4432. |
| Databáze: | OpenAIRE |
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