Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease requiring additional therapeutic strategies. MCL1, an anti-apoptotic BCL2 family member, promotes cancer-cell survival, but its role in mCRPC remains poorly understood. Here, we characterise MCL1 in multiple mCRPC biopsy cohorts and patient-derived models, assessing responses to MCL1 inhibition. MCL1 copy number gain (14%-34%) correlates with increased MCL1 expression and worse outcomes. MCL1 inhibition exhibits anti-tumour effects in MCL1-gained mCRPC models. Co-inhibition of MCL1 and AKT induces cancer-specific cell death in PTEN-loss/PI3K-activated models in vitro and in vivo, modulating BAD-BCLXL and BIM-MCL1 interactions, with durable anti-tumour activity in models with AKT inhibitor acquired resistance. Finally, CDK9-mediated MCL1 downregulation combined with AKT inhibition recapitulates these findings, providing further opportunities for clinical translation. These data support early phase clinical trials targeting MCL1, both as monotherapy for MCL1-gained mCRPC, and in combination with AKT inhibition for PTEN-loss/PI3K-activated mCRPC.
Authors
- George Seed (ORCID: https://orcid.org/0000-0002-1105-1781)
- Shana Y. Trostel (ORCID: https://orcid.org/0000-0002-5929-2576)
- Raul Miguel Luque (ORCID: https://orcid.org/0000-0002-7585-1913)
- Marco Bezzi (ORCID: https://orcid.org/0000-0001-9376-690X)
- Scott Wilkinson (ORCID: https://orcid.org/0000-0002-2613-8425)
- Craig J. Thomas (ORCID: https://orcid.org/0000-0001-9386-9001)
- Nathan A. Lack (ORCID: https://orcid.org/0000-0001-7399-5844)
- Roberta Paravati
- Ivan Pak Lok Yu
- Bora Gürel (ORCID: https://orcid.org/0000-0002-5018-8078)
- Daniel Westaby (ORCID: https://orcid.org/0000-0003-2996-4359)
- Antje Neeb (ORCID: https://orcid.org/0000-0002-6516-2938)
- Patricia C. Galipeau (ORCID: https://orcid.org/0000-0001-7961-7430)
- Ana Padilha (ORCID: https://orcid.org/0000-0003-0725-919X)
- Ilona Bernett
- Florian Gabel (ORCID: https://orcid.org/0000-0003-1768-7067)
- Ines Figueiredo (ORCID: https://orcid.org/0009-0007-2754-5608)
- Andreas Varkaris (ORCID: https://orcid.org/0000-0001-5776-8844)
- Gavin Ha (ORCID: https://orcid.org/0000-0001-7578-7272)
- Adam G. Sowalsky (ORCID: https://orcid.org/0000-0003-2760-1853)
- Ana Ferreira
- Mateus Crespo (ORCID: https://orcid.org/0000-0003-4043-8296)
- Carleen Klumpp‐Thomas (ORCID: https://orcid.org/0000-0002-6646-6132)
- Denisa Bogdan (ORCID: https://orcid.org/0000-0002-3017-4832)
- Nicole Pandell (ORCID: https://orcid.org/0000-0003-1182-4315)
- Jan Rekowski (ORCID: https://orcid.org/0000-0002-5207-3864)
- Amanda Swain (ORCID: https://orcid.org/0000-0001-8666-1608)
- Erica L. Beatson (ORCID: https://orcid.org/0000-0003-4517-906X)
- Florence I. Raynaud (ORCID: https://orcid.org/0000-0003-0957-6279)
- Antonio J. Montero‐Hidalgo (ORCID: https://orcid.org/0000-0002-1948-7512)
- Susana Miranda (ORCID: https://orcid.org/0000-0002-5936-2706)
- Wei Yuan (ORCID: https://orcid.org/0000-0001-8004-1846)
- Fatima Karzai (ORCID: https://orcid.org/0000-0002-3244-1332)
- Ruth Riisnaes (ORCID: https://orcid.org/0000-0002-8924-302X)
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- Souvik Das (ORCID: https://orcid.org/0000-0003-2206-1990)
- Adam Sharp (ORCID: https://orcid.org/0000-0002-3740-1612)
- Claudia Bertan (ORCID: https://orcid.org/0009-0009-2688-9067)
- John D. Taylor (ORCID: https://orcid.org/0000-0003-0095-0869)
- Johann Sebastian De Bono (ORCID: https://orcid.org/0000-0002-2034-595X)
- Lorenzo Buroni (ORCID: https://orcid.org/0000-0003-1999-4028)
- Ilsa M. Coleman (ORCID: https://orcid.org/0000-0002-1483-7202)
- William D. Figg (ORCID: https://orcid.org/0000-0003-2428-5613)
- Jon Welti
- Suzanne Carreira (ORCID: https://orcid.org/0000-0002-5077-5379)
- Steven P. Balk (ORCID: https://orcid.org/0000-0002-4546-7371)
- Melanie Valenti (ORCID: https://orcid.org/0000-0001-7610-1375)
- Emily Hobern
- Thomas Persse (ORCID: https://orcid.org/0009-0000-3209-592X)
- Xiaohu Zhang (ORCID: https://orcid.org/0000-0002-5329-1599)
- Jian Ning
- Cindy H. Chau (ORCID: https://orcid.org/0000-0002-6928-3833)
- Juan M. Jiménez-Vacas
- Nick Waldron
- Maryou B. Lambros
- Wanting Zeng (ORCID: https://orcid.org/0000-0002-4101-1502)
- Alexis de Haven Brandon
- Kate Liodaki (ORCID: https://orcid.org/0009-0001-9500-8093)
Institutions
- National Institutes of Health (US)
- Beth Israel Deaconess Medical Center (US)
- Koç University (TR)
- University of British Columbia (CA)
- Institute of Cancer Research (GB)
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (ES)
- Fred Hutch Cancer Center (US)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- Royal Marsden Hospital (GB)
- Hospital Universitario Reina Sofía (ES)
- National Cancer Institute (US)
- National Center for Advancing Translational Sciences (US)
- Center for Cancer Research (US)
- Cordoba University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-08
- DOI
- https://doi.org/10.1038/s41467-025-64042-5
- Citations
- 3
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 4.56
Funders
- U.S. Department of Health and Human Services
- American Association for Cancer Research
- Prostate Cancer Foundation
- University of Washington
- Movember Foundation
- Wellcome Trust
- Government of the United Kingdom
- Institute for Prostate Cancer Research
- Cancer Research UK
- National Institute for Health and Care Research
- Prostate Cancer UK
- National Institutes of Health
- Medical Research Council
- National Cancer Institute
- National Center for Advancing Translational Sciences