Abstract Treatment-induced shifts in prostate cancer (PCa) cell identity, known as lineage plasticity, lead to the emergence of tumors that may have little to no resemblance to the treatment-naïve tumors. In castration-resistant prostate cancer (CRPC), LP can manifest when androgen receptor (AR) -driven adenocarcinoma (CRPC-AR) differentiates into androgen-independent CRPC phenotypes. Along with genomic alterations, epigenetic mechanisms are also suggested to play an important role in this process. In this study, we focus on the role of the SWI/SNF chromatin remodeling complex. The SWI/SNF complex plays a fundamental role in development and lineage differentiation in adult and fetal cells, indicating its potential to modulate LP in cancer. In over 20% of cancers, this complex is genomically altered. Although genetic mutations of the complex are rare in prostate cancer, earlier studies from our lab showed increased and specialized expression of the SWI/SNF complex, particularly in the neuroendocrine phenotype of CRPC (CRPC-NE). Here, we investigate the role of the SWI/SNF complex in controlling lineage plasticity and whether targeting it represents a therapeutic vulnerability in CRPC-NE patients. Treatment of CRPC-NE organoids with either PROTAC SMARCA2/4 degrader (A947) or SMARCA2/4 inhibitor (BRM014) was not lethal but only decreased cell growth. Single-cell transcriptomics on CRPC-NE organoids after A947 treatment (SMARCA2/4 degradation) showed a decrease in the CRPC-NE gene expression signature, suggesting that the cell identity of these cells is disturbed by SWI/SNF inhibition. The transcription factor (TF) ASCL1 was recently described as a crucial player in driving lineage plasticity toward CRPC-NE. Interestingly, catalytic inhibition of the SWI/SNF complex completely erased ASCL1 protein expression in patient-derived CRPC-NE organoid models. SCENIC pathway analysis on single-cell transcriptomic data of CRPC-NE organoids after SMARCA2/4 degradation confirms a substantial decrease in TF activity of ASCL1. Thus, within CRPC-NE, the SWI/SNF complex regulates a key TF implicated in lineage plasticity, underscoring its importance in this process. To further study the importance of the SWI/SNF complex during lineage plasticity, we exploited the lineage-switching xenograft model used in Charles Sawyers' group, in which subcutaneously injected CRPC-Adeno organoids in mice develop into a CRPC-NE tumor (Romero et al. 2024, Nature Cancer). We performed IHC stainings at several time points during transition and subjected tumors to barcoded lineage tracing followed by single-cell RNA and ATAC sequencing. Following SWI/SNF subunit expression over time in this model system, this study confirmed the increasing dependency of the transitioning tumor on the SWI/SNF complex. In summary, our data suggest that the SWI/SNF complex might play an important role in the initiation of lineage plasticity and may represent one of the earliest hallmarks of this process during therapy resistance development in CRPC. Citation Format: Irene Paassen, Phillip Thienger, Andrej Benjak, Yuning Jackie. Tang, Monte Winslow, Mark Rubin. Deciphering the SWI/SNF complex: A crucial player in lineage plasticity and therapy resistance abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr PR006.
Paassen et al. (Tue,) studied this question.