Abstract 5834: The GR-LEDGF/p75 transcriptional network promotes therapy cross-resistance in prostate cancer cells

Abstract Prostate cancer (PCa) is the second leading cause of cancer mortality for men in the U. S. Patients who develop advanced PCa ultimately acquire therapy resistance and succumb to the disease. An emerging challenge in the treatment of advanced PCa is the development of therapy cross-resistance, in which molecular pathways promoting resistance to a particular drug or treatment also promote resistance to subsequent treatments. Although the mechanisms driving PCa therapy cross-resistance are not clearly understood, recent studies from our group and others implicate the glucocorticoid receptor (GR), a transcription factor, in resistance to both androgen receptor signaling inhibitors such enzalutamide (ENZ), and taxane drugs such as docetaxel (DTX). Our studies also showed that GR upregulates and interacts with the lens epithelium derived growth factor of 75 kD (LEDGF/p75) in a large panel of PCa cell lines. LEDGF/p75 is a stress transcription co-activator and oncoprotein that promotes cancer cell resistance to DTX and DNA-damaging drugs. GR and LEDGF/p75 are part of a large transcriptional network that include other oncogenic transcription factors linked to cancer chemoresistance such as β-catenin, Menin, MLL, JPO2, and c-Myc. We hypothesized that this transcriptional network plays a role in PCa therapy cross-resistance and could be a promising therapeutic target. We observed by Western blotting (WB) that both GR and LEDGF/p75 proteins are upregulated in ENZ-resistant and DTX-resistant PCa cell lines, and that GR silencing in both contexts abrogated LEDGF/p75 expression. MTT viability assays showed that ENZ-resistant PCa cells also exhibited cross-resistance to DTX. Bioinformatics studies, using publicly available RNA-seq datasets, identified overlapping differentially expressed genes (DEGs) between ENZ-resistant and DTX-resistant PCa cells. Individual silencing of GR and LEDGF/p75 in two DTX-resistant PCa cell lines followed by RNA-seq analysis also identified an overlap between DEGs regulated by GR and LEDGF/p75 with DEGs associated with both ENZ and DTX resistance in PCa. GSEA analysis of DEGs targeted by both GR and LEDGF/p75 in DTX-resistant PCa cells revealed enriched pathways associated with stress responses, androgen responses, and regulation of cell death and cell cycle. Further, we initiated studies to evaluate the efficacy of small molecule inhibitors targeting multiple components of the GR-LEDGF/p75 transcriptional network in sensitizing therapy-resistant PCa cells to DTX and ENZ. In conclusion, our results implicate the GR-LEDGF/p75 axis in promoting resistance to both ENZ and DTX in PCa cells. Further mining of RNA-seq data will identify potential molecular targets associated with PCa therapy cross-resistance, leading to the design of novel therapeutic strategies to attenuate this resistance. 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 promotes therapy cross-resistance in prostate cancer cells 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 (6Suppl): Abstract nr 5834.