ECE2024 Oral Communications Oral Communications 13: Late Breaking (6 abstracts)
BCL2 expression is enriched in androgen receptor-negative advanced prostate cancer:
Juan M Jiménez-Vacas 1 , Daniel Westaby 1,2 , Ines Figueiredo 1 , Jan Rekowski 1 , Claire Pettinger 2 , Bora Gurel 1 , Denisa Bogdan 1 , Lorenzo Buroni 1 , Antje Neeb 1 , Ana Padilha 1 , Joe Taylor 1 , Wanting Zeng 1 , Souvik Das 1 , Emily Hobern 1 , Ruth Riisnaes 1 , Mateus Crespo 1 , Susana Miranda 1 , Ana Ferreira 1 , Brian Hanratty 3 , Daniel Nava Rodrigues 1 , Claudia Bertan 1 , George Seed 1 , Maria de Los Dolores Fenor de La Maza 1,2 , Christina Guo 1,2 , Juliet Carmichael 1,2 , Rafael Grochot 1,2 , Khobe Chandran 1,2 , Anastasia Stavridi 4 , Andreas Varkaris 4 , Nataly Stylianou 5 , Brett Hollier 5 , Nina Tunariu 1,2 , Steven Balk 4 , Suzanne Carreira 1 , Wei Yuan 1 , Peter Nelson 3,6 , Eva Corey 6 , Michael Haffner 3,6 , Johann de Bono 1,2 & Adam Sharp 1,2
1The Institute of Cancer Research, London, United Kingdom; 2The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; 3Fred Hutchinson Cancer Center, Seattle, United States; 4Beth Israel Deaconess Medical Center, Boston, United States; 5Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Brisbane, Australia; 6University of Washington, Seattle, United States
Background: Treatment resistance in prostate cancer can be the result of multiple different tumour cell adaptations generating castration-resistant prostate cancer (CRPC). Despite advancements in treatment, CRPC remains a highly lethal disease. Some CRPCs become AR independent with loss of AR expression and lineage plasticity, urgently requiring novel therapeutic strategies. BCL2 can be upregulated in some CRPCs and may be a therapeutic target for this disease subset.
Objective: To characterise BCL2 expression in late stage CRPC, determine its association with AR expression, uncover its mechanisms of regulation, elucidate their clinical significance, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility.
Methods: AR and BCL2 protein expression were determined by immunohistochemistry (IHC) in two separate CRPC cohorts. IHC data were correlated with clinical outcomes. IHC for neuroendocrine markers was performed in a subset of tumours. Whole genome bisulfite sequencing (WGBS), RNA sequencing, and chromatin immunoprecipitation (ChIP) data from multiple independent CRPC cohorts were analysed. Finally, PC cell lines and patient-derived xenograft (PDX) models were characterised and treated with BH3-mimetics in vitro.
Results: AR protein loss emerged with castration resistance and was detected in 4.8% of metastatic CRPC (mCRPC), associating with shorter overall survival (OS). BCL2 expression was primarily detected in AR-negative mCRPC, and associated with shorter OS, and with resistance to AR-signalling inhibitors (ARSIs) but not docetaxel. High BCL2 expression associated with lineage plasticity features and neuroendocrine marker positivity. BCL2 expression was regulated by DNA methylation and increased by Snail and the neuronal transcription factor ASCL1. BCL2 inhibition has anti-tumour activity in some, but not all, BCL2-positive PC models. Simultaneously targeting other antiapoptotic proteins, including BCLXL and MCL1, resulted in rapid apoptotic cell death.
Conclusions: BCL2 expression is enriched in AR-negative mCRPC with features of lineage plasticity, and associated with worse clinical outcomes, with BCL2-positive mCRPC appearing more sensitive to docetaxel than ARSI. BCL2 expression is regulated by DNA methylation and driven by Snail and ASCL1. BCL2 inhibition has anti-tumour activity in some, but not all, BCL2-positive PC models identifying the need for combination strategies that selectively target tumour cell apoptosis to enhance response to therapy.
Volume 99
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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