BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity
The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response.
Authors
- Cláudia Bertan (ORCID: https://orcid.org/0000-0003-4211-0649)
- George Seed (ORCID: https://orcid.org/0000-0002-1105-1781)
- Rafael Grochot (ORCID: https://orcid.org/0000-0002-2156-9197)
- Wei Yuan (ORCID: https://orcid.org/0000-0001-5694-8835)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Bora Gürel (ORCID: https://orcid.org/0000-0002-5018-8078)
- Daniel Westaby (ORCID: https://orcid.org/0000-0003-2996-4359)
- Nataly Stylianou (ORCID: https://orcid.org/0000-0002-8006-5730)
- Antje Neeb (ORCID: https://orcid.org/0000-0002-6516-2938)
- Ana Padilha (ORCID: https://orcid.org/0000-0003-0725-919X)
- Arian Lundberg (ORCID: https://orcid.org/0000-0002-6630-2787)
- Juan M. Jiménez‐Vacas (ORCID: https://orcid.org/0000-0003-4391-3726)
- Christina Guo (ORCID: https://orcid.org/0000-0002-1645-3202)
- Andreas Varkaris (ORCID: https://orcid.org/0000-0001-5776-8844)
- Brian Hanratty (ORCID: https://orcid.org/0000-0003-4580-649X)
- Mateus Crespo (ORCID: https://orcid.org/0000-0003-4043-8296)
- Denisa Bogdan (ORCID: https://orcid.org/0000-0002-3017-4832)
- Jan Rekowski (ORCID: https://orcid.org/0000-0002-5207-3864)
- Nina Tunariu (ORCID: https://orcid.org/0000-0001-6656-3699)
- Brett G. Hollier (ORCID: https://orcid.org/0000-0002-1204-6001)
- Michael C. Haffner (ORCID: https://orcid.org/0000-0003-0809-6425)
- Susana Miranda (ORCID: https://orcid.org/0000-0002-5936-2706)
- Ana Ferreira (ORCID: https://orcid.org/0000-0002-7844-2760)
- 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)
- 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)
- Daniel Nava Rodrigues (ORCID: https://orcid.org/0009-0003-9872-1008)
- Suzanne Carreira (ORCID: https://orcid.org/0000-0002-5077-5379)
- Anastasia Stavridi
- Emily Hobern
- Maria D. Fenor de la Maza (ORCID: https://orcid.org/0000-0002-0971-8954)
- Ines Figueiredo (ORCID: https://orcid.org/0009-0007-7334-7362)
- Khobe Chandran
- Wanting Zeng (ORCID: https://orcid.org/0000-0002-4101-1502)
- Claire Pettinger
- Juliet Carmichael
- Steven P Balk
Institutions
- Beth Israel Deaconess Medical Center (US)
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- Queensland University of Technology (AU)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1172/jci179998
- Citations
- 19
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 7.96
Funders
- U.S. Department of Defense
- V Foundation for Cancer Research
- American Society of Clinical Oncology
- Movember Foundation
- Wellcome Trust
- Institute for Prostate Cancer Research
- Cancer Research UK
- Prostate Cancer UK
- Ministerstvo Životního Prostředí
- Ministarstvo Civilnih Poslova Bosne i Hercegovine
- Medical Research Council