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 1

Loss of AR protein expression occurs in a small subset of CRPC and associates with poor prognosis.

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Loss of AR protein expression occurs in a small subset of CRPC and assoc...
(A) Summary of clinical samples analyzed for the ICR/RMH CRPC IHC patient cohort. A total of 187 mCRPC biopsies and 60 matched same-patient CSPC biopsies were analyzed. Clinical outcome data, including OS from CRPC diagnosis and CRPC biopsy date, were collected for all 187 patients. (A–D) IHC for nuclear AR-NTD was performed in 187 CRPC biopsies and 60 matched, same-patient CSPC tumors. (B) Representative micrographs for matched, same-patient samples are shown with examples of emergent loss (patient 68) and increased (patient 151) and stable (patient 169) AR-NTD protein expression. Scale bar: 50 μm. HS, H score. (C and D) Nuclear AR-NTD protein expression (H score) in 60 matched, same-patient CSPC and CRPC tumors (C) and 187 CRPC tumors (D). Medians and interquartile ranges (IQRs) are shown. Wilcoxon’s matched-pairs signed-rank test was used to determine statistical significance. Red lines highlight cases of AR-NTD–negative CRPC and their matched CSPC sample. The threshold for AR negativity (H score ≤ 20) is highlighted in blue. A heterogeneous case with 2 tumor cell populations (AR positive and AR negative) is highlighted in orange and included twice. (E) Kaplan-Meier OS curves from time of CRPC diagnosis, split by AR-positive (H score > 20) and AR-negative (H score ≤ 20) tumors. HR with 95% CIs and P value for log-rank test are shown. *The heterogeneous case is included in the AR-NTD–negative group.