Abstract C096: The GR-LEDGF/p75 transcriptional network as a promising target to reduce therapy cross-resistance in prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the second-leading cause of cancer mortality in U.S. men, with African American (AA) men showing higher incidence and mortality compared to European American men. In addition, AA men are more likely to be diagnosed with more aggressive PCa resulting in reduction of treatment options, especially as tumors develop therapy resistance. Thus, understanding the mechanisms underlying PCa therapy resistance is crucial for developing new therapeutic options. The upregulation of the Lens Epithelium Derived Growth Factor p75 (LEDGF/p75) by glucocorticoid receptor (GR) is a novel mechanism of PCa therapy resistance recently identified by our group. GR upregulation in PCa bypasses the blockade of androgen receptor by inhibitors such as enzalutamide and abiraterone. LEDGF/p75 is an oncogenic transcription co-activator that promotes DNA damage repair and cancer cell survival against environmental stressors including chemotherapeutic drugs such as docetaxel (DTX). An emerging concern in PCa treatment is therapy cross-resistance, in which the molecular mechanisms of resistance to a particular drug confer resistance to another drug. Our recent studies showed that GR upregulates and interacts with LEDGF/p75 forming a transcriptional complex that includes other oncoproteins such as Menin, JPO2, c-Myc and HRP2, and promotes DTX resistance (DTX-R) in PCa cells. In addition, we reported that both GR and LEDGF/p75 are upregulated in enzalutamide resistant (ENZ-R) PCa cells. We hypothesized that the GR- LEDGF/p75 transcriptional network plays a role in PCa therapy cross-resistance to both ENZ and DTX and is a promising therapeutic target. Cell viability assays revealed that ENZ-R in PCa cells confers cross-resistance to DTX. Western blot analysis revealed upregulation of members of the GR-LEDGF/p75 network such as GR, LEDGF/p75, Menin and c-Myc in ENZ-R PCa cells, consistent with similar observations in DTX-R PCa cells. Upon knockdown of GR and LEDGF/p75 in DTX-R PCa cells, we identified by RNA-seq analysis overlapping DEGs associated with both ENZ-R and DTX-R, suggesting that the GR-LEDGF/p75 transcriptional network may contribute to therapy cross-resistance. Consistent with this, mining of publicly available RNA-seq databases identified 46 overlapping differentially expressed genes (DEGs) between ENZ-R and DTX-R PCa cells. Pathway analysis of DEGs regulated by both GR and LEDGF/p75 revealed significant enrichment of Apoptosis, p53, and DNA repair pathways, which are associated with therapy resistance. Ongoing studies are evaluating the anti-cancer properties and synergistic/additive potential of various inhibitors of the GR-LEDGF/p75 transcriptional network in cellular models of ENZ-R and DTX-R. These studies provide novel mechanistic insights into PCa therapy cross-resistance and may lead to the development of novel therapeutic strategies to reduce PCa mortality disparities. Citation Format: Pedro T. Ochoa, Evelyn S. Sanchez-Hernandez, Kai Wen Cheng, Isaac Kremsky, Charles Wang, Carlos A. Casiano. The GR-LEDGF/p75 transcriptional network as a promising target to reduce therapy cross-resistance in prostate cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C096.