Abstract C115: Understanding the role of <i>PSIP1</i>/<i>LEDGF</i>p75 in prostate cancer therapy resistance and race-related disparities

Abstract Background: LEDGFp75 (lens epithelium-derived growth factor), encoded by the PSIP1 gene, is a transcriptional co-activator and chromatin reader that is regulated by glucocorticoid receptor (GR) signaling and implicated in resistance to taxanes and androgen receptor signaling inhibitor (ARSI) drugs in pre-clinical prostate cancer (PCa) models. This study explores the associations between PSIP1 gene expression, therapy resistance, clinical outcomes, and racial differences in PCa, with the goal of uncovering molecular contributors to disparities in treatment response among diverse patient populations. Methods: 7,875 prostate tumors underwent Next-Gen sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). Tumors were stratified into PSIP1 high and low subgroups based on median expression. RNA expression was used to profile the tumor microenvironment (TME) using QuantiSEQ. Significance calculated using chi-square, Fisher’s exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (q&amp;lt;0.05). Overall survival (OS) from time of tissue collection and time-on-treatment (TOT) estimated from insurance claims data using the Cox proportional hazards model to calculate hazard ratio (HR) and log-rank tests to calculate P values. Results: The cohort was comprised of 63% Non-Hispanic White patients (NHW, N=4951), 15% African Americans (AA, N=1171), 3% Asian/Pacific Islander (API, N=207) and 20% Other (N=1546). Median PSIP1 expression was lower in AA compared to NHW patients (38.7 vs 40.2 TPM, p=0.03). In the TME, high PSIP1 expression was associated with higher infiltration of M2 macrophages, B cells, NK cells, Myeloid dendritic cells, Tregs and Neutrophils when compared to low expression regardless of race (p&amp;lt;0.001). In AA patients, RB1 mutations were more common in PSIP1-high tumors compared to -low (4.5% vs 0.6%, p&amp;lt;0.05), while PSIP1-high tumors less frequently harbored mutations in RNF43 (0.9% vs 2.9%, p&amp;lt;0.05) and SPOP (11.0% vs 16.0%, p&amp;lt;0.05). In NHW patients, RB1 and TP53 mutations were more common in PSIP1-high tumors vs -low (6.2% vs 2.0% and 37.6% vs 32.2%, respectively, p&amp;lt;0.001), while several genes mutations were less common in PSIP1-high tumors (SPOP: 8.7% vs 10.9%; MSH2: 2.7% vs 10.5%; p&amp;lt;0.05). In API patients, high PSIP1 expressors had great prevalence of mutations in IDH1 (6.0% vs 0.0%, p&amp;lt;0.05) and JAK1 (9.6% vs 2.1%, p&amp;lt;0.05). In NHW patients, high PSIP1 expressors had shorter OS (HR 1.2, 95% CI 1.1-1.3, p&amp;lt;0.001) and shorter TOT with ARSI drugs (HR 1.2, 95% CI 1.1-1.3, p=0.002) compared to low expressors. No significant differences in OS were observed in AA or API patients. Conclusion: Our data shows a distinct TME for PSIP1-high expressors vs low expressors in PCa regardless of race. However, distinct race-related differences were observed in PSIP1 expression, mutational landscape, OS and TOT for ARSI drugs. These differences highlight the important role of PSIP1 in PCa and its implications for therapy resistance in a health disparity context. Citation Format: Yasmine Baca, Pedro T. Ochoa Alfonso Duran, Frankis Almaguel, Rana R. McKay, Andrew Elliott, Ninad Kulkarni, Norm Smith, Matthew Oberley, Carlos A. Casiano. Understanding the role of PSIP1/LEDGFp75 in prostate cancer therapy resistance and race-related disparities [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C115.