Abstract B020: BCL2 expression is enriched in AR-independent advanced prostate cancer

Abstract Background The widespread use of highly potent androgen receptor (AR) inhibitors has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC). AR independence, typically driven by loss of AR expression and/or trans-differentiation to a neuroendocrine or basal phenotype, lacks effective therapeutic strategies. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine tumours and has been proposed as a therapeutic target for this subset of advanced prostate cancers. Objective To characterise AR expression in advanced PC, to evaluate its association with BCL2, to elucidate their clinical significance, and to explore whether BCL2 may represent a valid therapeutic target and/or biomarker. Methods AR and BCL2 expression were immunohistochemically scored in two independent CRPC cohorts (431 biopsies from 247 patients), including 62 matched same-patient castration-sensitive PC (CSPC) biopsies. Scores were associated with retrospectively collected clinical data including overall survival (OS) and response to AR-targeting therapy. BCL2 protein expression was also determined in 28 primary prostate samples (19 patients). Transcriptome data from two independent CRPC cohorts were analysed, including for associations between BCL2 expression and gene expression signatures. A patient-derived xenograft-organoid (PDX-O) CRPC model with high expression of BCL2 was treated with multiple BH3 mimetics. Results and limitations We demonstrate that AR protein loss emerges with castration resistance and occurs in subset of metastatic CRPC (mCRPC) (5%) associating with worse OS (51 vs 18 months from CRPC diagnosis, hazard ratio [HR] 5.52 [2.83-10.78], p<0.001). BCL2 protein expression is enriched in AR-negative mCRPC (p<0.001), associating with worse OS (53 vs 19 months from CRPC diagnosis, HR 2.80 [1.40-5.57], p=0.002) and resistance to AR-targeting therapy (≥50% PSA response: 48% vs 13%), irrespective of AR expression status. BCL2 mRNA expression associates with several key signalling pathways known to promote stemness and lineage plasticity, including EMT and IL6/JAK/STAT3. Furthermore, BCL2 is enriched in basal prostate cells, whose expression profile has been linked with aggressive subtypes of mCRPC, including small cell neuroendocrine CPRC. We show that a high BCL2-expressing PDX-O is resistant to BCL2 inhibition, with functional redundancy between the anti-apoptotic BCL2 family proteins. BCLXL and MCL1 are highly expressed in BCL2-positive mCRPC and may drive resistance to BCL2 targeting. Utilising a post-mortem mCRPC biopsy cohort, we show intra-patient heterogeneity in BCL2 expression. These findings highlight the need for combination therapies. Further studies are required to dissect the interaction between AR and BCL2, and to probe the functional role of BCL2 in this subset of mCRPC. Conclusions BCL2-positivity associates with AR-independence, worse OS, and resistance to AR-targeting in CRPC. Combination strategies are required to optimise response to BCL2 inhibition and to combat heterogeneity. Citation Format: Daniel Westaby, Juan M. Jimenez-Vacas, Ines Figueiredo, Claire Pettinger, Bora Gurel, Denisa Bogdan, Jan Rekowski, Lorenzo Buroni, Antje Neeb, Ruth Riisnaes, Mateus Crespo, Susana Miranda, Ana Ferreira, Daniel Nava Rodrigues, George Seed, Claudia Bertan, Maria de los Dolores Fenor de la Maza, Christina Guo, Juliet Carmichael, Rafael Grochot, Khobe Chandran, Andreas Varkaris, Steven P. Balk, Wei Yuan, Suzanne Carreira, Peter S. Nelson, Michael Haffner, Eva Corey, Johann de Bono, Adam Sharp. BCL2 expression is enriched in AR-independent advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B020.