Targeting Androgen Receptor in Her2-Driven Breast Cancer

Presentation Number: OR07-4
Date of Presentation: June 15th, 2013

Nicholas D'Amato*1, Hui Lyu1, Bolin Liu1, Haihua Gu1, Andrew Protter2, Anthony Elias3 and Jennifer K Richer1
1University of Colorado Anschutz Medical Campus, Aurora, CO, 2Medivation Inc., San Francisco, CA, 3Univ of Colorado Anschutz Medical Campus, Aurora, CO

Abstract

Introduction: The androgen receptor (AR) is expressed in approximately 60% of Her2+ breast cancers. Activated AR elicits transcriptional upregulation of Her3. Her3 can heterodimerize with Her2, is essential for growth of Her2+ tumors, and has been implicated in therapeutic resistance to tamoxifen, paclitaxel, and trastuzumab. Enzalutamide (ENZA) is an anti-androgen that impairs nuclear entry of liganded AR, binds to AR with higher affinity than bicalutamide, and was recently approved for treatment of castrate-resistant prostate cancer.

Hypothesis: ENZA will enhance the efficacy of trastuzumab in Her2+ breast cancer lines by inhibiting Her3 expression.

Methods:We tested both estrogen receptor positive and negative Her2+ (amplified or overexpressing without amplification) breast cancer cell lines for androgen-induced upregulation of Her3 protein and inhibition of proliferation with trastuzumab or ENZA alone as compared to the two drugs combined. Resistance to trastuzumab was generated in two Her2+ breast cancer cell lines (SKBR3 and BT474) and these lines were also tested.

Results: Dihydrotestosterone (DHT) induced an increase in total Her3 and phospho-Her3 in some Her2+ BC cell lines and this effect was inhibited by the addition of ENZA.  The combination of ENZA and trastuzumab inhibited proliferation more effectively than either agent alone in the ER-/Her2+ MDA-MB-453, SUM185E, and SKBR3 cell lines. Interestingly, ENZA inhibited proliferation in MDA-MB-453 and SUM185PE cells (Her2 overexpression without amplification) as well or better than trastuzumab, whereas trastuzumab showed a greater inhibitory effect than ENZA in SKBR3 cells (Her2 amplified). In the ER+/AR+/Her2 amplified BT474 cell line, the combination of ENZA and trastuzumab inhibited proliferation significantly more than either drug alone. In the trastuzumab resistant lines, where trastuzumab alone is ineffective, ENZA combined with trastuzumab significantly inhibited proliferation.

Conclusions:  Our results suggest that ENZA may serve as an effective therapeutic in Her2+ breast cancer when combined with Her2-directed therapies such as trastuzumab, pertuzumab, or T-DM1. Furthermore, in tumors resistant to Her2 directed therapy, ENZA may be useful alone or in combination with anti-Her3 therapy. Targeting AR with ENZA in patients with Her2+ disease may result in therapeutic benefit and warrants clinical investigation.

 

Disclosure: AP: Employee, Medivation. Nothing to Disclose: ND, HL, BL, HG, AE, JKR