Abstract 3589: Understanding the role of Pax5 in development of taxane-resistant NE-like prostate cancer

Abstract Background: Resistance to the existing Androgen Receptor Signaling Inhibitor (ARSI) therapies led to higher incidences of aggressive therapy-induced neuroendocrine-like prostate cancer (t-NEPC) with predominant small cell-like characteristics, dismal overall survival, and an ultimate resistance to taxane chemotherapies. t-NEPCs are mostly treated with platinum-based drugs with etoposide and/or taxane but have less selectivity and high systemic toxicity, which often limits their clinical and therapeutic potential. During t-NEPC transformation, upon chromatin reprogramming associated with epigenetic alterations and altered transcriptional activity, adenocarcinoma loses its luminal features to adopt neurobasal characteristics. The following study aims to unravel the mechanism of developing t-NEPC taxane resistance upon acquiring such adaptive neuronal characteristics. Objective: The primary objective is to delineate how chromatin modifications along with epigenetic regulation facilitates the adaptive neuronal characteristics and dictates the development of t-NEPC taxane resistance. Methods: We generated various t-NEPC cell lines either by genetic modification (DKD) or therapeutic pressure (C4-2BER). We performed RNA-Seq, ATAC-Seq and acetylated Histone (H3K18 and H3K27) ChIP-Seq in our developed t-NEPC models and compared with adenocarcinoma. We next compared ATAC Seq and Acetylated histone ChIP Seq with RNA Seq in C4-2B and C4-2BER and performed functional assays. Results: Our ATAC Seq and acetylated histone footprints (Ac H3K18 and Ac H3K27 ChIP Seq) analyses revealed an enhanced chromatin accessibility during t-NEPC transformation. Overlapping RNA seq suggested newly transcribed neuronal genes with higher extent of promoter accessibility. Transcription Factor mapping among newly accessible gene promoters revealed preferential Pax5 binding, whose expression occurs selectively in t-NEPC unlike adenocarcinoma. Pathway analysis of differentially expressed neuronal genes in t-NEPC suggested an involvement of Pax5 in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are essential for strong cellular communication. Furthermore, Pax5 depletion disrupts cellular interaction in t-NEPC, thereby, sensitizing them to taxane therapies. Conclusions: Our study concludes that continuous AR ablation with ARSIs, leads to chromatin alterations with epigenetic changes, thereby allowing Pax5 transcriptional activation in t-NEPC. This altered transcriptional activity promotes gene expression necessary to govern taxane-resistant t-NEPC development. Citation Format: Sreyashi Bhattacharya, Ridwan Islam, Sanika Bodas, Juhi Mishra, Dipanwita Das, Kaustubh Datta, Samikshan Dutta. Understanding the role of Pax5 in development of taxane-resistant NE-like prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3589.