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Abstract P6-20-04: Activation of AR inhibits growth of endocrine-resistant breast cancer

Introduction Resistance to endocrine therapy is a major clinical problem in estrogen receptor positive (ER+) breast cancer. The androgen receptor (AR) is expressed in ˜90% of all ER+ breast cancers and high expression of AR is associated with a better patient outcome in this subtype. In agreement, AR activation in breast cancer cell line models reduces proliferation of cells via antagonism of ER signaling. However, uncertainty surrounding the role of AR in endocrine resistance is reflected in current clinical trials in which both AR agonists and antagonists are being investigated. In this study, we sought to investigate the optimal approach in targeting AR in endocrine-resistant breast cancer. Methods We evaluated the consequences of AR activation, using AR cognate ligand 5α-dihydrotestosterone (DHT) and selective AR modulator enobosarm, and AR antagonism using enzalutamide on in vitro and in vivo models of endocrine-resistance. The efficacy of these AR modulators were assessed in vitro using tamoxifen-resistant (TamR) and long-term estrogen derived (LTED) models of MCF7 cells, and in vivo using ESR1 mutant E2-dependent (HCI-005) and ESR1 wild-type E2-independent (Gar15-13) endocrine-resistant PDX models Results Treatment with DHT and enobosarm inhibited the growth of MCF7 TamR and LTED cells but enzalutamide had no effect. AR activation was associated with loss of ER in MCF7 TamR cells and loss of ER-regulated PR expression in MCF7 LTED which suggests that this growth suppression was mediated through the antagonism of ER signaling. Notably, an additive anti-proliferative effect was observed with the combination of enobosarm and CDK4/6 inhibitor palbocilib in the MCF7 TamR cells. A similar pattern was observed in vivo with DHT strongly inhibiting the proliferation of both PDX models. Enobosarm similarly suppressed the proliferation of HCI-005, and to a lesser extent in Gar15-13. The benefit of enobosarm in Gar15-13 was significant given that this model is fulvestrant-resistant. Antagonizing AR with enzalutamide had no effect on growth of Gar15-13 model, similar to our in vitro data. AR agonists reduced expression levels of ER and PR in HCI-005, and transcriptomic analysis of AR agonist-treated Gar15-13 identified significant negative enrichment of genes related to proliferation and estrogen response. These observations indicate that the growth-suppressive effects of AR activation in vivo were mediated through inhibiting ER signaling. We identified an AR gene signature, through RNA-seq analysis of DHT-treated Gar15-13 PDX, which is strongly associated with good outcome in the METABRIC dataset, supporting the hypothesis that an active canonical AR signaling is tumor suppressive in both endocrine-sensitive and -resistant disease contexts. Lastly, we present in vivo data demonstrating enhanced suppression of Ki-67 with the combination of enobosarm and palbociclib in the Gar15-13 PDX. Conclusion We have demonstrated that activating AR is an effective therapeutic approach in endocrine-resistant breast cancer, and the combination of an AR agonist with a CDK4/6 inhibitor warrants further investigation in this breast cancer subtype. Citation Format: Chia KM, Milioli H, Portman N, Laven-Law G, Yong A, Swarbrick A, Caldon L, Tilley W, Hickey T, Lim E. Activation of AR inhibits growth of endocrine-resistant breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-04.