Abstract 332: AKT1 mediated post translational modification of the glucocorticoid receptor drives resistance to prostate cancer therapy.

Abstract Increasing evidence shows that resistance to androgen-deprivation therapy (ADT) and next-generation androgen receptor (AR) antagonists in advanced prostate cancers develops partly through compensatory activation of alternative nuclear hormone receptors. Notably, induction of the glucocorticoid receptor (GR) has been demonstrated in both preclinical and clinical studies to confer resistance to AR-targeted therapies. Although total GR is crucial for tissue homeostasis and normal inflammatory responses, our preliminary GR-phospho proteomics data reveal that, under enzalutamide resistance, GR undergoes increased phosphorylation, especially at serine-134 (p-GR(s134)), suggesting a post-translational mechanism driving a pro-oncogenic GR activation in therapy-resistant tumors. We have previously shown that inhibiting AKT signaling, GR expression, and its pro-oncogenic activity restores sensitivity to AR-directed therapy. Predictions from PhosphoNET.ca and functional studies identify AKT1 as the AKT isoform responsible for phosphorylating GR at S134. Importantly, both functional and pharmacologic inhibition of AKT1 reduced GR phosphorylation at s134 without affecting total GR protein levels. While GR can be activated by ligands such as dexamethasone, our data suggest that, in PCa cells that adopt GR compensatory signaling for survival, GR activation is mediated by AKT1 phosphorylation. Overall, our data show that suppression of pGR-s134 activity renders these cancer cells re-vulnerable to AR-targeted drugs such as enzalutamide and enhances their response to GR modulators. Citation Format: Surendra Gulla, Tej Sharma, Ephraim Gardner, Abbas Jawadala, Sasikumar Ponnusamy, Tobi Ogunbowale, Maddie Aust, Jonathan E. Bard, Remi Adelaiye-Ogala. AKT1 mediated post translational modification of the glucocorticoid receptor drives resistance to prostate cancer therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 332.