Journal Article

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

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

2024

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Androgen receptors / Androgens / Animals / Antimitotic agents / Antineoplastic agents / Antitumor activity / Apoptosis / ASCL1 protein / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Bcl-2 protein / Biomarkers / Biopsy / Cancer cells / Castration / Cell culture / Cell Line, Tumor / Cell Lineage / DNA Methylation / Epithelial-Mesenchymal Transition / FDA approval / Gene Expression Regulation, Neoplastic / Genetic aspects / Genetic transcription / Health aspects / Humans / Leukemia / Male / Mann-Whitney U test / Medical prognosis / Medical research / Medicine, Experimental / Membrane proteins / Metastases / Metastasis / Methylation / Mice / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Neuroendocrine tumors / Oncology / Patients / Phenotypes / Phenotypic plasticity / Physiological aspects / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - metabolism / Prostatic Neoplasms, Castration-Resistant - pathology / Protein expression / Proteins / Proto-Oncogene Proteins c-bcl-2 - genetics / Proto-Oncogene Proteins c-bcl-2 - metabolism / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Stem cells / Therapeutic targets / Tumors