Preclinical characterization of abemaciclib in hormone receptor positive breast cancer

// Raquel Torres-Guzman 1 , Bruna Calsina 1 , Ana Hermoso 1 , Carmen Baquero 1 , Beatriz Alvarez 1 , Joaquin Amat 1 , Ann M. McNulty 2 , Xueqian Gong 2 , Karsten Boehnke 1 , Jian Du 2 , Alfonso de Dios 3 , Richard P. Beckmann 2 , Sean Buchanan 2 and Maria Jose Lallena 1 1 Quantitative Biology, Eli Lilly and Company, Madrid, Spain 2 Oncology Research, Eli Lilly and Company, Indianapolis, Indiana, USA 3 Discovery Chemistry, Eli Lilly and Company, Indianapolis, Indiana, USA Correspondence to: Maria Jose Lallena, email: lallena_maria_jose@lilly.com Keywords: abemaciclib, cell cycle, hormone receptor positive breast cancer, senescence, apoptosis Received: October 06, 2016      Accepted: April 24, 2017      Published: May 10, 2017 ABSTRACT Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for CDK4 and CDK6 that has shown antitumor activity as a single agent in hormone receptor positive (HR+) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using in vitro and in vivo breast cancer models. Treatment of estrogen receptor positive (ER+) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, and a decrease in cell proliferation. Moreover, abemaciclib exposure led to durable inhibition of pRb, TopoIIα expression and DNA synthesis, which were maintained after drug removal. Treatment of ER+ breast cancer cells also led to a senescence response as indicated by accumulation of β-galactosidase, formation of senescence-associated heterochromatin foci, and a decrease in FOXM1 positive cells. Continuous exposure to abemaciclib altered breast cancer cell metabolism and induced apoptosis. In a xenograft model of ER+ breast cancer, abemaciclib monotherapy caused regression of tumor growth. Overall these data indicate that abemaciclib is a CDK4 and CDK6 inhibitor that, as a single agent, blocks breast cancer cell progression, and upon longer treatment can lead to sustained antitumor effects through the induction of senescence, apoptosis, and alteration of cellular metabolism.