Oncotarget

Research Papers:

Preclinical characterization of abemaciclib in hormone receptor positive breast cancer

Raquel Torres-Guzmán, Bruna Calsina, Ana Hermoso, Carmen Baquero, Beatriz Alvarez, Joaquín Amat, Ann M. McNulty, Xueqian Gong, Karsten Boehnke, Jian Du, Alfonso de Dios, Richard P. Beckmann, Sean Buchanan and María José Lallena _

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Oncotarget. 2017; 8:69493-69507. https://doi.org/10.18632/oncotarget.17778

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Abstract

Raquel Torres-Guzmán1, Bruna Calsina1, Ana Hermoso1, Carmen Baquero1, Beatriz Alvarez1, Joaquín Amat1, Ann M. McNulty2, Xueqian Gong2, Karsten Boehnke1, Jian Du2, Alfonso de Dios3, Richard P. Beckmann2, Sean Buchanan2 and María José Lallena1

1Quantitative Biology, Eli Lilly and Company, Madrid, Spain

2Oncology Research, Eli Lilly and Company, Indianapolis, Indiana, USA

3Discovery Chemistry, Eli Lilly and Company, Indianapolis, Indiana, USA

Correspondence to:

María José Lallena, email: [email protected]

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.


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