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Continuous treatment with abemaciclib leads to sustained and efficient inhibition of breast cancer cell proliferation

2022; Impact Journals LLC; Volume: 13; Issue: 1 Linguagem: Inglês

10.18632/oncotarget.28249

1949-2553

Raquel Torres-Guzmán, Maria Patricia Ganado, Cecilia Mur, Carlos Marugán, Carmen Baquero, Yanzhu Yang, Yi Arial Zeng, Huimin Bian, Jian Du, Alfonso de Dios, Óscar Puig, Marı́a José Lallena,

Cancer-related Molecular Pathways

// Raquel Torres-Guzmán 1 , Maria Patricia Ganado 1 , Cecilia Mur 1 , Carlos Marugan 1 , Carmen Baquero 1 , Yanzhu Yang 2 , Yi Zeng 2 , Huimin Bian 2 , Jian Du 2 , Alfonso de Dios 2 , Oscar Puig 3 and María José Lallena 1 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 Correspondence to: María José Lallena, email: lallena_maria_jose@lilly.com Keywords: abemaciclib; breast cancer; cell lines; CDK4/6; continuous dosing Received: March 17, 2022     Accepted: June 14, 2022     Published: July 02, 2022 Copyright: © 2022 Torres-Guzmán et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT 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.