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15357163mct170290-sup-181312_2_supp_4555481_p3ssbb.xlsx (55.03 kB)

Table S3, S4 and S5 from Preclinical Activity of Abemaciclib Alone or in Combination with Antimitotic and Targeted Therapies in Breast Cancer

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posted on 2023-04-03, 16:07 authored by Neil O'Brien, Dylan Conklin, Richard Beckmann, Tong Luo, Kevin Chau, Josh Thomas, Ann Mc Nulty, Christophe Marchal, Ondrej Kalous, Erika von Euw, Sara Hurvitz, Colleen Mockbee, Dennis J. Slamon

File containing three supplemental tables listing the mean tumor volumes and responses in the ER+/HER2-, HER2+/ER+ and TNBC xenografts

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ARTICLE 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.

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