Preclinical Activity of Abemaciclib Alone or in Combination with Antimitotic and Targeted Therapies in Breast Cancer

Mol Cancer Ther. 2018 May;17(5):897-907. doi: 10.1158/1535-7163.MCT-17-0290. Epub 2018 Feb 26.

Abstract

The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2- and ER+/HER2+ subtypes. However, a subset of triple-negative breast cancer (TNBC) cell lines with intact Rb signaling were also found to be responsive. Equivalent levels of tumor growth inhibition were observed in ER+/HER2-, ER+/HER2+ as well as biomarker selected TNBC xenografts in response to abemaciclib. In addition, abemaciclib combined with hormonal blockade and/or HER2-targeted therapy induced significantly improved antitumor activity. CDK4/6 inhibition with abemaciclib combined with antimitotic agents, both in vitro and in vivo, did not antagonize the effect of either agent. Finally, we identified a set of Rb/E2F-regulated genes that consistently track with growth inhibitory response and constitute potential pharmacodynamic biomarkers of response to abemaciclib. Taken together, these data represent a comprehensive analysis of the preclinical activity of abemaciclib, used alone or in combination, in human breast cancer models. The subtypes most likely to respond to abemaciclib-based therapies can be identified by measurement of a specific set of biomarkers associated with increased dependency on cyclinD:CDK4/6:Rb signaling. These data support the clinical development of abemaciclib as monotherapy or as a combination partner in selected ER+/HER2-, HER2+/ER+, and TNBCs. Mol Cancer Ther; 17(5); 897-907. ©2018 AACR.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminopyridines / administration & dosage
  • Aminopyridines / pharmacology*
  • Animals
  • Antimitotic Agents / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor / methods
  • Female
  • Humans
  • MCF-7 Cells
  • Mice, Nude
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays / methods

Substances

  • Aminopyridines
  • Antimitotic Agents
  • Benzimidazoles
  • Receptors, Estrogen
  • abemaciclib
  • Receptor, ErbB-2