Abstract 4409: Exploring PBX1's role in enzalutamide resistance in advanced prostate cancer

作者：E. A. Gardner, Surendra Gulla, Leslie McClinton, Jonathan Bard, Remi Adelaiye‐Ogala · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-4409 · 被引用次数：1 · 研究领域：Prostate Cancer Treatment and Research

Aggressive prostate cancer (PCa) is often driven by upscaled activity of the androgen receptor (AR), and second-generation AR antagonists such as Enzalutamide have become standard therapeutics for men with advanced PCa. While patients initially respond to treatment, many develop resistance, with disease progression and poor prognosis. We have focused on a mechanism involving an AR cistrome switch from a canonical to a non-canonical cistrome as PCa becomes Enzalutamide-resistant. As collaborating protein partners drive transcriptional activity, we employed core regulatory circuitry analysis in Enzalutamide-resistant PCa cell line models to identify novel Transcription Factor (TF) candidates that may be involved in non-canonical AR cistrome reprogramming. One identified candidate is Pre B-Cell Leukemia Homeobox 1 (PBX1), a TALE homeodomain TF involved in embryonic development and cellular differentiation. PBX1 is known to work with other TFs to modulate gene expression and has been implicated as an oncogenic driver in hematologic and solid cancers, including PCa. Our group has shown that PBX1 is highly expressed in prostate cancer cell line models of castrate- and Enzalutamide-resistance compared to Enzalutamide-sensitive models. Through multi-ome single-cell ATAC + gene expression analysis of a heterogenous patient-derived xenograft (PDX) model, we identified clusters of cells that are enriched for PBX1, AR, and non-canonical AR target CREB5, while simultaneously expressing lo...