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Updated: Jun 13, 2025
Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture
Published on: November 22, 2019
BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity
Daniel Westaby1,2, Juan M Jiménez-Vacas1, Ines Figueiredo1
1The Institute of Cancer Research, London, United Kingdom.
Abstract:
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.
Insights
Androgen receptor signaling inhibitors (ARSIs) resistance in prostate cancer (PC) can lead to AR-independent disease. This study shows BCL2 is upregulated in AR-negative metastatic CRPC, correlating with poor survival and suggesting BCL2 inhibition as a therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Potent androgen receptor signaling inhibitors (ARSIs) drive castration-resistant prostate cancer (CRPC) towards AR-independent phenotypes.
- Neuroendocrine prostate cancer (NEPC) subsets exhibit upregulated BCL2, presenting a potential therapeutic target.
- Clinical characterization of BCL2 in metastatic CRPC (mCRPC) is needed to assess its role and therapeutic utility.
Purpose of the Study:
- To clinically characterize BCL2 expression in mCRPC.
- To determine the association of BCL2 with AR expression and lineage plasticity.
- To investigate BCL2 regulation and evaluate its potential as a therapeutic target.
Main Methods:
- Analysis of multiple prostate cancer biopsy cohorts and preclinical models.
- Assessment of BCL2 expression in relation to AR status, survival, and clinical features.
- Investigation of BCL2 regulation via DNA methylation and transcription factors (ASCL1).
- Evaluation of BCL2 inhibition efficacy in preclinical models.
Main Results:
- BCL2 expression is enriched in AR-negative mCRPC, correlating with shorter overall survival and ARSI resistance.
- High BCL2 expression is associated with lineage plasticity and neuroendocrine markers.
- BCL2 regulation involves DNA methylation and the transcription factor ASCL1.
- BCL2 inhibition demonstrated antitumor activity in a subset of models, indicating potential but also limitations.
Conclusions:
- BCL2 is a key marker and potential therapeutic target in AR-negative mCRPC.
- Understanding BCL2 regulation is crucial for developing effective treatment strategies.
- Combination therapies targeting BCL2 may be necessary to overcome resistance and enhance efficacy in aggressive prostate cancer.
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