Activity of Combined Androgen Receptor Antagonism and Cell Cycle Inhibition in Androgen Receptor Positive Triple Negative Breast Cancer.

Autor:	Christenson JL; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., O'Neill KI; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Williams MM; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Spoelstra NS; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Jones KL; Deparment of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma., Trahan GD; Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Reese J; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Van Patten ET; School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Elias A; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Eisner JR; Innocrin Pharmaceuticals, Inc., Durham, North Carolina., Richer JK; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. jennifer.richer@cuanschutz.edu.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 Jun; Vol. 20 (6), pp. 1062-1071. Date of Electronic Publication: 2021 Mar 15.
DOI:	10.1158/1535-7163.MCT-20-0807
Abstrakt:	Triple-negative breast cancer (TNBC) is an aggressive subtype, with a peak recurrence rate within the first few years after diagnosis. Few targeted therapies are available to treat this breast cancer subtype, defined by the lack of estrogen receptor (ER) and progesterone receptor and without amplification of human epidermal growth factor receptor 2 (HER2). Although cell cycle cyclin-dependent kinase (CDK) 4/6 inhibitors are approved for treatment of ER-positive (ER + ) breast cancer, they have not proven effective as monotherapy in patients with TNBC. The androgen receptor (AR) has emerged as a therapeutic target in a subset of TNBCs and with significant clinical benefit observed in multiple trials. The purpose of this study was to investigate the preclinical activity of the CDK4/6 inhibitor, abemaciclib, in combination with an agent that targets both androgen biosynthesis and AR activity, seviteronel, using TNBC cell lines expressing high AR, cell line xenografts, and an AR-positive (AR + ), androgen-responsive TNBC patient-derived xenograft (PDX). Single-cell RNA sequencing demonstrated heterogeneity in AR levels, even in a highly AR + cell line, and identified cell cycle pathway activation in AR High - versus AR Low -expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor, abemaciclib, and seviteronel showed synergy in an AR + TNBC model compared with each drug alone. Although cell cycle inhibitors are FDA approved for use in ER + breast cancer, our studies suggest that they may also be effective in AR + TNBC, perhaps combined with AR-targeted agents. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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