Exploiting androgen receptor agonism as a treatment strategy in estrogen receptor-positive metastatic breast cancer
The androgen receptor (AR) is expressed in 75% of estrogen receptor-positive (ER+) breast cancers (BC). Selective AR modulators (SARMs), like EP0062, present a promising therapeutic strategy for ER + BC, particularly in patients who cannot tolerate endocrine therapy (ET) or whose tumors have developed resistance. We aimed to study the antitumor activity of EP0062 in ER+ patient-derived xenograft (PDX) models. EP0062 displayed comparable antitumor efficacy to selective ER degraders (SERDs), including in PDXs with ESR1, PIK3CA, or PTEN mutations. Tumors sensitive to SARMs were enriched in GATA3 mutations. EP0062 treatment induced AR-target genes across all models tested. A transcriptional signature associated with SARM sensitivity was identified, primarily driven by proliferation-related processes, consistent with a significant decrease in S-phase cell cycle proteins upon treatment in EP0062-sensitive models. In some EP0062-resistant tumors, the combination with palbociclib enhanced the antitumor effect of EP0062, suggesting a potential strategy for metastatic patients with acquired ET resistance.
Authors
- Motoki Takaku (ORCID: https://orcid.org/0000-0002-8652-2541)
- Laia Monserrat (ORCID: https://orcid.org/0000-0002-8802-3033)
- Flaminia Pedretti (ORCID: https://orcid.org/0009-0002-4855-6078)
- Aerica Nagornyuk
- Eduardo García‐Galea (ORCID: https://orcid.org/0000-0003-4699-0786)
- Sarat Chandarlapaty (ORCID: https://orcid.org/0000-0003-4532-8053)
- Cristina Molina (ORCID: https://orcid.org/0000-0003-1547-8528)
- Olga Rodríguez (ORCID: https://orcid.org/0000-0002-0123-9975)
- Mafalda Oliveira (ORCID: https://orcid.org/0000-0001-9152-8799)
- Lara Nonell (ORCID: https://orcid.org/0000-0002-8538-8213)
- Andreu Òdena (ORCID: https://orcid.org/0000-0003-1529-880X)
- V Serra
- Cristina Saura (ORCID: https://orcid.org/0000-0001-8296-5065)
- Cristina Viaplana (ORCID: https://orcid.org/0000-0001-8904-4330)
- Marta Guzmán (ORCID: https://orcid.org/0000-0002-0924-9887)
- Rodrigo Dienstmann (ORCID: https://orcid.org/0000-0001-5997-318X)
- Judith García-García
- Meritxell Bellet
- Gilles Flamen
- Irene Agustí-Barea
- Fara Brasó-Maristany
- Julia Ponomarenko
- Taras Yuziv Duda
- Ruth Maldonado-Padrol
- Aleix Prat
- Claudia Yáñez-Bartolomé
- Guillermo P. Vicent
Institutions
- Universitat de Vic - Universitat Central de Catalunya (ES)
- Hebron University (PS)
- Memorial Sloan Kettering Cancer Center (US)
- Consejo Superior de Investigaciones Científicas (ES)
- Universitat Pompeu Fabra (ES)
- University of North Dakota (US)
- Vall d'Hebron Institut de Recerca (ES)
- Hospital Clínic de Barcelona (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Centre for Genomic Regulation (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Institut de Biologia Molecular de Barcelona (ES)
- Vall d'Hebron Institute of Oncology (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- npj Breast Cancer
- Published
- 2026-06-17
- DOI
- https://doi.org/10.1038/s41523-026-00993-2
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Cancer Society
- Fundación BBVA
- Fundación Cellex
- “la Caixa” Foundation
- Ministerio de Ciencia, Innovación y Universidades
- Centres de Recerca de Catalunya
- European Commission
- Fundación Científica Asociación Española Contra el Cáncer
- Generalitat de Catalunya
- Banco Bilbao Vizcaya Argentaria
- Fundación General CSIC
- Fundació Institut de Recerca Hospital Universitari Vall d’Hebron
- Fundación Fero
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación