BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity
Daniel Westaby, … , Johann de Bono, Adam Sharp
Daniel Westaby, … , Johann de Bono, Adam Sharp
Published September 17, 2024
Citation Information: J Clin Invest. 2024;134(18):e179998. https://doi.org/10.1172/JCI179998.
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Research Article Oncology

BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity

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.

Authors

Daniel Westaby, Juan M. Jiménez-Vacas, Ines Figueiredo, Jan Rekowski, Claire Pettinger, Bora Gurel, Arian Lundberg, Denisa Bogdan, Lorenzo Buroni, Antje Neeb, Ana Padilha, Joe Taylor, Wanting Zeng, Souvik Das, Emily Hobern, Ruth Riisnaes, Mateus Crespo, Susana Miranda, Ana Ferreira, Brian P. Hanratty, Daniel Nava Rodrigues, Claudia Bertan, George Seed, Maria de Los Dolores Fenor de La Maza, Christina Guo, Juliet Carmichael, Rafael Grochot, Khobe Chandran, Anastasia Stavridi, Andreas Varkaris, Nataly Stylianou, Brett G. Hollier, Nina Tunariu, Steven P. Balk, Suzanne Carreira, Wei Yuan, Peter S. Nelson, Eva Corey, Michael Haffner, Johann de Bono, Adam Sharp

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Figure 2

BCL2 protein expression is enriched in AR-negative disease and associates with poor prognosis.

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BCL2 protein expression is enriched in AR-negative disease and associate...
(A–D) IHC for BCL2 was performed on 47 CRPC biopsies, with preexisting AR-NTD (ICR/RMH CRPC IHC cohort). (A) Representative micrographs are shown. Scale bar: 50 μm. HS, H score. (B) Cytoplasmic BCL2 expression split by AR expression status: AR negative (AR-NTD H score ≤ 20, n = 8) and AR positive (AR-NTD H score > 20, n = 40). Median and IQRs are shown. Mann-Whitney U test was used. (C) Percentage of BCL2-positive (H score > 20) and BCL2-negative (H score ≤ 20) tumors split by AR expression status as above. Fisher’s exact test was used. *The heterogeneous case with 2 tumor cell populations (AR-positive/BCL2-negative and AR-negative/BCL2-positive) is included twice (highlighted orange). (D) H scores for nuclear AR-NTD and cytoplasmic BCL2 expression. (E and F) BCL2 mRNA expression in AR-low (AR mRNA ≤20th percentile) and AR-high (AR mRNA >20th percentile) mCRPC in the SU2C/PCF (n = 210) (E) and SU2C/WCDT (n = 159) (F) cohorts. Medians and IQRs are shown. Mann-Whitney U test was used. (G) Kaplan-Meier survival curves from time of CRPC diagnosis, split by BCL2-positive and BCL2-negative tumors. HR with 95% CIs and P value for log-rank test are shown. *The heterogeneous case is included in the BCL2-positive group. (H and I) AR-NTD and BCL2 IHC was performed on 485 spatially separated samples from 177 mCRPC sites taken at rapid autopsy (58 patients). (H) Representative micrographs with examples of intrapatient inter-metastatic site heterogeneity. Scale bar: 50 μm. (I) Cytoplasmic BCL2 expression (OD) split by AR-negative (OD ≤ 0.013, n = 50) and AR-positive (OD > 0.013, n = 127) tumors. Average OD scores for all samples from each mCRPC tissue were used for this analysis. The threshold for BCL2 negativity (OD ≤ 0.033) is highlighted in blue. Median and IQRs are shown. Mann-Whitney U test was used to determine statistical significance.