Abstract 1953: Posttranslational modification in glucocorticoid receptor in treatment resistant prostate cancers

Abstract Prostate Cancer (PCa) remains the most common cancer in men in the United States and the second leading cause of cancer-related death in men. An evolving concept that contributes to our understanding of resistance to androgen deprivation therapy (ADT) and AR antagonists in advanced PCa is the ability of cells to turn on compensatory hormone receptor signaling for survival. Preclinical and clinical studies demonstrate that induction of glucocorticoid receptor (GR) expression confers resistance to AR-targeted therapy. Previous studies from our lab demonstrated that the inhibition of AKT signaling blocks pro-oncogenic GR activity and overcomes resistance to AR-targeted therapy. AKT1 is predicted to phosphorylate GR at s134, however, the implications of pGR(s134) in advanced PCa remains unclear. Although ligands (e.g., Dex) activates GR, we have found GR activation modulated by post-translational modification (PTM) and persistent in treatment resistant PCa. Therefore, we hypothesize pro-oncogenic GR activation through AKT1-induced PTM. The rationale is that by inhibiting AKT signaling, we block residual GR signaling that can potentially drive lethal prostate cancers and consequently be re-sensitized to the standard of care. We validated our findings by Western blot analysis, we used an AKT1-specific inhibitor (AKT1i) and observed decreased AKT1 activity and decreased pGR(s134) without affecting total GR protein expression. Functional studies using shRNA against AKT1 showed reduced pGR(s134) expression without affecting the total GR expression Our preliminary data suggests that pro-oncogenic GR activity is modulated through the phosphorylation of GR on s134 by AKT1. Citation Format: Surendra Gulla, Ephraim Gardner, Shreya Shyam Sundar, Praveen Jaiswal, Ning Gao, Lynda Bennet, Suzanne Conzen, Remi Adelaiye-Ogala. Posttranslational modification in glucocorticoid receptor in treatment resistant prostate cancers [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(6_Suppl):Abstract nr 1953.