Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor-Positive Breast Cancer Models with a Distinct Mechanism of Action

Clin Cancer Res. 2017 Dec 15;23(24):7608-7620. doi: 10.1158/1078-0432.CCR-17-0670. Epub 2017 Oct 3.


Purpose: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer, eliciting favorable response. The current study evaluates the activity and efficacy of the oral selective AR modulator RAD140 in in vivo and in vitro models of AR/ER+ breast cancer.Experimental Design: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER+ breast cancer xenograft models.Results: RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER+ breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER+ PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication was suppressed with RAD140 treatment, an effect apparently enhanced by concurrent administration of palbociclib.Conclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of ESR1 It inhibits the growth of multiple AR/ER+ breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER+ breast cancer patients. Clin Cancer Res; 23(24); 7608-20. ©2017 AACR.

MeSH terms

  • Androgens / pharmacology*
  • Androgens / therapeutic use
  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogens
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Nitriles / pharmacology*
  • Nitriles / therapeutic use
  • Oxadiazoles / pharmacology*
  • Oxadiazoles / therapeutic use
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Xenograft Model Antitumor Assays


  • Androgens
  • Estrogen Receptor alpha
  • Estrogens
  • Nitriles
  • Oxadiazoles
  • Receptors, Androgen
  • RAD140