Activity of combined androgen receptor antagonism and cell cycle inhibition in androgen receptor-positive triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype, with a peak recurrence rate within the first few years post diagnosis. Few targeted therapies are available to treat this breast cancer (BC) subtype, defined by the lack of estrogen and progesterone receptors (ER and PR) and without amplification of human epidermal growth factor receptor 2 (HER2). While cell cycle cyclin dependent kinase (CDK) 4/6 inhibitors are approved for treatment of ER-positive BC, 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 TNBC and with significant clinical benefit observed in multiple trials. The purpose of this study was to investigate the pre-clinical 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, 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 ARHigh versus ARLow expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor abemaciclib and seviteronel showed synergy in an AR+ TNBC model compared to each drug alone. Implications. While cell cycle inhibitors are FDA-approved for use in ER-positive breast cancer, our studies suggest that they may also be effective in AR+ TNBC, perhaps combined with AR targeted agents.