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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 Article has an altmetric score of 48

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

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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 6

BCL2 expression is regulated by DNA methylation in mCRPC.

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BCL2 expression is regulated by DNA methylation in mCRPC.
(A–C) Whole-ge...
(A–C) Whole-genome bisulfite sequencing (WGBS) in 36 LuCaP PDXs. (A) WGBS tracks from a BCL2-negative (LuCaP 77, blue) and a BCL2-positive (LuCaP 93, red) tumor. The differentially methylated region (DMR) on the BCL2 promoter is highlighted in orange. (B) Methylation index (0–1) split by BCL2-negative (OD ≤ 0.033, n = 23) and BCL2-positive (OD > 0.033, n = 13) tumors. Colors denote different molecular phenotypes. Mann-Whitney U test was used to determine statistical significance. (C) Heatmap depicting BCL2 protein expression, BCL2 mRNA expression, and methylation index for the LuCaP PDXs. Tumors are organized by molecular phenotype (color bars) and then ordered by BCL2 protein expression. (D–F) WGBS in the SU2C/WCDT mCRPC patient cohort (n = 48). (D) WGBS tracks from a BCL2-low (DTB-020, blue) and a BCL2-high (DTB-036, red) tumor. (E) Methylation index (0–1) split by BCL2-low (<90th percentile mRNA expression, n = 43) and BCL2-high (≥90th percentile mRNA expression, n = 5) tumors. Colors denote different molecular phenotypes. Mann-Whitney U test was used to determine statistical significance. (F) Heatmap depicting BCL2 mRNA expression and methylation index in SU2C/WCDT mCRPC cohort. Tumors are grouped by molecular phenotype as determined using the AR, NEURO I, and NEURO II gene expression sets.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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