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 3

BCL2 positivity associates with resistance to ARSI and poor prognosis in mCRPC irrespective of AR expression status, but there is no difference in response to docetaxel.

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BCL2 positivity associates with resistance to ARSI and poor prognosis in...
(A–D) Clinical outcome data, including best PSA response, time on ARSI, and OS from starting ARSI, were collected for 36 patients. (A) Top: Waterfall plot of greatest percentage fall in PSA from baseline for 29 patients treated with either abiraterone or enzalutamide, split by BCL2 negative (blue, n = 21) and BCL2 positive (red, n = 8). *No response. Bottom: Pie charts showing percentage of patients with BCL2-negative and BCL2-positive CRPC that had a ≥50% fall in PSA from baseline. (B and C) Kaplan-Meier curves, split by BCL2-positive (H score > 20) and BCL2-negative (H score ≤ 20) tumors, showing time on ARSI (B) and OS from initiation of ARSI (C). (D) Kaplan-Meier curves, split by BCL2-positive/AR-negative, BCL2-positive/AR-positive, and BCL2-negative, for OS from initiation of ARSI. *The heterogeneous case is included in the BCL2-positive (and BCL2-positive/AR-negative) group. (E and F) Clinical outcome data, including best PSA response, time on docetaxel, number of docetaxel cycles, and OS from starting docetaxel, were collected for 36 patients. Kaplan-Meier curves, split by BCL2-positive (H score > 20) and BCL2-negative (H score ≤ 20) tumors, showing time on docetaxel (E) and OS from initiation of docetaxel (F). HR with 95% CIs and P values for the log-rank test are shown for Kaplan-Meier curves.