Continuous treatment with abemaciclib leads to sustained and efficient inhibition of breast cancer cell proliferation
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Raquel Torres-Guzmán1, Maria Patricia Ganado1, Cecilia Mur1, Carlos Marugan1, Carmen Baquero1, Yanzhu Yang2, Yi Zeng2, Huimin Bian2, Jian Du2, Alfonso de Dios2, Oscar Puig3 and María José Lallena1
1 Discovery Chemistry Research and Technology, Eli Lilly and Company, Madrid, Spain
2 Eli Lilly and Company, Indianapolis, IN 46225, USA
3 Eli Lilly and Company, New York, NY 10016, USA
|María José Lallena,||email:||[email protected]|
Keywords: abemaciclib; breast cancer; cell lines; CDK4/6; continuous dosing
Received: March 17, 2022 Accepted: June 14, 2022 Published: July 02, 2022
Abemaciclib is an oral, selective cyclin-dependent kinase 4 & 6 inhibitor (CDK4 & 6i), approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) as monotherapy for endocrine refractory disease, and with endocrine therapy (ET) for initial treatment and after progression on ET. Abemaciclib has also shown clinical activity in combination with ET in patients with high risk early BC (EBC). Here, we examined the preclinical attributes of abemaciclib and other CDK4 & 6i using biochemical and cell-based assays. In vitro, abemaciclib preferentially inhibited CDK4 kinase activity versus CDK6, resulting in inhibition of cell proliferation in a panel of BC cell lines with higher average potency than palbociclib or ribociclib. Abemaciclib showed activity regardless of HER2 amplification and phosphatidylinositol 3-kinase (PI3KCA) gene mutation status. In human bone marrow progenitor cells, abemaciclib showed lower impact on myeloid maturation than other CDK4 & 6i when tested at unbound concentrations similar to those observed in clinical trials. Continuous abemaciclib treatment provided profound inhibition of cell proliferation, and triggered senescence and apoptosis. These preclinical results support the unique efficacy and safety profile of abemaciclib observed in clinical trials.
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