Abstract 6713: RB1 and TP53 restrict lineage plasticity in prostate cancer by regulating chromatin accessibility

Abstract Lineage plasticity has been widely recognized in various cancers as a driver of therapeutic resistance, but the molecular basis of this plasticity remains incompletely defined. Evidence from the literature reveals that the inactivation of RB1 and TP53 in prostate cancer (PC) results in the emergence of alternative lineage states that are resistant to androgen receptor (AR)-targeted treatment. How RB1 and TP53 loss cause this lineage plasticity is not clear. This study proposes that RB1 and TP53 help maintain heterochromatin in order to restrict chromatin accessibility and maintain the fidelity of lineage specific gene expression. To test this hypothesis, changes in chromatin accessibility (ATAC-seq) and lineage gene expression (RNA-seq) are monitored in single prostate organoid cells over time following deletion of PTEN (SKO) or PTEN/RB1/TP53 (TKO). Analysis of resulting data indicates that TKO organoids have increased transcriptional diversity and elevated expression pathways like JAK-STAT that have been functionally linked to lineage plasticity and resistance to AR-targeted therapies. These gene expression changes are preceded by increased chromatin accessibility at relevant gene promoters. Enrichment of neuroendocrine PC gene signatures is found in both SKO and TKO organoids likely driven by histone methyltransferase EZH2 as well as DNA methyltransferase DNMT1. TKO organoids also exhibit increased ability to adapt to changing growth conditions, likely facilitated by their increased transcriptional plasticity. Future directions for this study will assess the influence of EZH2 and DNMT1 on chromatin accessibility, gene expression, lineage plasticity, and therapeutic resistance following tumor suppressor deletion. Overall, results are consistent with the hypothesis that RB1 and TP53 loss in PC cells creates a more accessible chromatin state permissive for transcription. Findings may also reveal approaches to suppress therapeutic resistance in PC by therapeutic targeting of lineage plasticity. Citation Format: Mauricio Rodrigo Flores, David W. Goodrich, Justine Jacobi. RB1 and TP53 restrict lineage plasticity in prostate cancer by regulating chromatin accessibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6713.