Preclinical characterization of abemaciclib in hormone receptor positive breast cancer.

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

doi:10.18632/oncotarget.17778

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.

Highlights

Components of the cyclin-dependent kinase 4 (CDK4)/CDK6/Cyclin D/retinoblastoma (Rb)/p16INK4a pathway function in multiple processes implicated in cancer, including cell proliferation, senescence, apoptosis, and cellular metabolism [1,2,3,4]
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
Evidence from breast cancer mouse models suggests that Cyclin D1, and CDK4 and CDK6 activation contribute to suppressing senescence, as Cyclin D1 ablation in these models after tumor formation led to an onset of senescence in the isolated tumor cells, as did treatment with a CDK4 and CDK6 inhibitor [6]

Summary

Introduction

Components of the cyclin-dependent kinase 4 (CDK4)/CDK6/Cyclin D/retinoblastoma (Rb)/p16INK4a pathway function in multiple processes implicated in cancer, including cell proliferation, senescence, apoptosis, and cellular metabolism [1,2,3,4]. The catalytic proteins CDK4 and CDK6, work with their activating partners, D type cyclins, to phosphorylate the Rb tumor suppressor protein. This phosphorylation of Rb by CDK4/CDK6/ Cyclin D, and subsequently by CDK2/Cyclin E, leads to the dissociation of the transcription factor E2F, and release of transcriptional repression of genes important for DNA synthesis and S phase progression [3, 5]. Evidence from breast cancer mouse models suggests that Cyclin D1, and CDK4 and CDK6 activation contribute to suppressing senescence, as Cyclin D1 ablation in these models after tumor formation led to an onset of senescence in the isolated tumor cells, as did treatment with a CDK4 and CDK6 inhibitor [6]. At least one of the downstream mechanisms by which CDK4 and CDK6 suppress senescence is by activating and stabilizing the forkhead transcription factor, FOXM1, through multi-site phosphorylation [8]

Methods

Results

Conclusion