Abstract 1455: The glucocorticoid receptor-LEDGFp75 interaction in prostate cancer therapy cross-resistance

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer deaths in the U.S., disproportionally affecting African American (AA) men. PCa patients with recurrent disease develop therapy resistance and fail to respond to both anti-androgen receptor signaling (ARSI) therapy and taxane-based chemotherapy. Glucocorticoid receptor, a transcription factor, has been implicated in resistance to ARSI (via the GR bypass), and docetaxel (DTX) therapies. However, the mechanisms underlying this GR-mediated therapy cross-resistance are poorly understood. Previously, we demonstrated that glucocorticoids, which are co-administered with current PCa therapies and activate GR signaling, upregulate the chemoresistance-associated transcription coactivator LEDGFp75 in PCa cells. We also identified consensus GR binding sites in the promoter region of the gene encoding LEDGFp75, suggesting it is a GR target gene. We hypothesized that GR transcriptionally upregulates LEDGFp75 and then interacts with this protein in the nucleus to promote DTX resistance in PCa cells. Genetic silencing of GR in a panel of DTX-sensitive and -resistant PCa cell lines decreased the expression of LEDGFp75 at both the protein and transcript levels, confirming its status as a candidate GR target gene. However, genetic silencing of LEDGFp75 had no effects on GR protein expression. Pharmacological inhibition of GR also decreased LEDGFp75 in DTX-sensitive cells. The effects of Exicorilant and Relacorilant (Corcept Therapeutics) were evaluated on LEDGFp75 protein expression levels. Immunoprecipitation and confocal microscopy studies revealed that GR and LEDGFp75 interact in the nucleus of PCa cells. Interestingly, upregulation of GR in enzalutamide resistant LNCaP cells correlated with LEDGFp75 upregulation, and GR silencing in these cells decreased this upregulation. These results suggested a possible role for GR and LEDGFp75 in PCa therapy cross-resistance. Further studies are underway to determine if co-targeting these two proteins genetically and pharmacologically attenuates both enzalutamide resistance and DTX resistance and other aggressive properties of PCa cells. In addition, RNAseq studies have been initiated to determine the degree of transcriptional overlap between GR and LEDGFp75 in chemoresistant PCa cells. Our goal is to link mechanistically the GR-LEDGFp75 transcriptional network to ARSI/taxane cross-resistance in PCa and target this network to attenuate therapy resistance. Citation Format: Evelyn S. Sanchez-Hernandez, Pedro T. Ochoa, Greisha L. Ortiz-Hernandez, Shannalee Martinez, Carlos Casiano. The glucocorticoid receptor-LEDGFp75 interaction in prostate cancer therapy cross-resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1455.