Abstract 1719: Constitutive aryl hydrocarbon activity promotes resistance to bortezomib which is exacerbated by leptin and potentially involves Src phosphorylation by JAK2 in prostate cancer cells

Abstract The aryl hydrocarbon receptor (AhR) plays a role in regulating diet-induced obesity and is a nuclear transcription factor involved in the transcriptional regulation of target genes, such as enzymes of xenobiotic metabolism (CYP1, UGTs) or genes involved in the transcriptional regulation. Induced enzymes facilitate the metabolism of various endogenous compounds and drugs, such as bortezomib. We report that the constitutive activity of AhR promotes drug resistance which is exacerbated in the presence of leptin and potentially involves AhR-mediated Src phosphorylation by JAK2 in a prostate cancer in vitro model. Leptin is known to contribute to cancer progression and has an emerging role in chemoresistance. Of note, both leptin receptor and aryl hydrocarbon receptor are overexpressed in prostate cancer cell lines. Additionally, our lab previously reported an integrative bioinformatics analysis using TCGA data (n=498) which revealed a positive correlation in AHR and LEPR mRNA expression in patients with prostate cancer. Our in vitro results also show AhR protects androgen-insensitive C4-2 cells but not LNCaP cells from apoptosis induced by anti-androgens, suggesting AhR activity leads to androgen independence and potentially multi-class chemoresistance. Further investigation into AhR as a drug target in obesity-associated conditions for the treatment of advanced prostate cancer upon entering the phase of drug resistance coupled with failure of first-line androgen deprivation therapy. Citation Format: Kofi K. Khamit-Kush, Daniel J. Walters, Nathan J. Bowen, Jeffrey A. Handy, Joann B. Powell. Constitutive aryl hydrocarbon activity promotes resistance to bortezomib which is exacerbated by leptin and potentially involves Src phosphorylation by JAK2 in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1719.