Abstract 3144: Targeting AR-SREBP crosstalk in prostate adenocarcinoma

Abstract Androgen receptor (AR) is a well-studied nuclear transcription factor responsible for the progression of prostate cancer. Prostate Cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among men in the United States, despite the availability of advanced AR inhibitors. Hence, there is an urgent need to identify alternative therapeutic targets and agents to supplement AR-based therapy. Sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors, consisting of SREBP-1 and SREBP-2, that are responsible for de novo lipogenesis and cholesterol biosynthesis. Recent studies show that crosstalk between AR and SREBP promotes PCa progression. Consistent with this, we have observed that SREBP is overexpressed in the presence of AR. Therefore, we hypothesized that pharmacological inhibition of SREBPs might be a promising therapeutic approach in androgen receptor-positive PCa. In our study, we evaluated the anticancer activity of fatostatin, an SREBP inhibitor, in AR-positive PCa cell lines (LNCaP and C4) and AR-negative PCa cell lines (PC3 and Du145). We observed inhibition of viability, proliferation, migration, and invasion in all PCa cell lines. Additionally, we observed decreased protein and mRNA expression of SREBPs and AR in the fatostatin treatment group. Notably, fatostatin showed significantly more potent inhibition in AR-positive PCa cell lines compared to AR-negative PCa cell lines. To further understand the molecular mechanism of fatostatin in AR-positive PCa cell lines, we performed RNA-Seq, which revealed inhibition of AR signaling and cholesterol homeostasis. It was also observed that genes involved in mitotic spindle assembly and the mTORC1 pathway have been downregulated. Altogether, our data show that pharmacological inhibition of SREBP may be a potential therapeutic target in AR-positive prostate cancer. Citation Format: Sirisha Devarakonda,Prashanth Parupathi,Ekniel Francois,Avinash Kumar. Targeting AR-SREBP crosstalk in prostate adenocarcinoma [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 3144.