SAT-095 Screening For Therapeutic Targets To Suppress GH Production And Proliferation In AIP Mutant GH-producing Cells

Abstract Disclosure: T. Tanaka: None. T. Fukuda: None. H. Fujii: None. D. Kawanami: None. S. Kodama: None. T. Yanase: None. Germline mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) predispose to pituitary adenomas, mainly somatotropinomas. These AIP germline mutations have been identified in 15-20% of patients with familial isolated pituitary adenoma (FIPA) and in 3-5% of patients with sporadic pituitary adenomas. Patients with AIP mutations tend to develop pituitary tumors at an early age, which are often large and aggressive. Standard treatment includes surgery, medical therapy, and radiation therapy. However, these tumors may exhibit reduced responsiveness to somatostatin analogs, posing challenges for effective disease management in some cases. Our previous study identified a heterozygous frameshift mutation resulting in a premature stop codon as the cause of familial acromegaly, and we genetically modified the rat GH-producing pituitary tumor cell line (GH3) to establish an AIP-deficient subline, GH3-FTY, which harbors compound heterozygous frameshift mutations. The GH-producing activity of GH3-FTY was 20-43-fold higher than that of the parental GH3, accompanied by increased STAT3 (Tyr705) phosphorylation and resistance to somatostatin. In this study, we utilized GH3-FTY cells to explore potential therapeutic targets. A total of 361 anticancer agents and pathway-specific inhibitors were tested, and Gh1 mRNA expression was quantified by RT-qPCR. Among these, cucurbitacin I (a JAK2 inhibitor) and cytochalasin D (an actin polymerization inhibitor) significantly suppressed Gh1 mRNA expression and GH secretion. Both agents also inhibited GH3-FTY cell proliferation and increased caspase-3/7 activity. Western blot analysis demonstrated that cucurbitacin I and cytochalasin D reduced STAT3 phosphorylation levels. The POU domain transcription factor POU1F1 (also known as Pit1), which is essential for anterior pituitary development and regulates transcription of pituitary hormones including GH, prolactin (PRL), and thyroid-stimulating hormone beta (TSHb). Cucurbitacin I downregulated POU1F1 expression at both mRNA and protein levels, suggesting that GH1 suppression is mediated through POU1F1 downregulation. These findings indicate the JAK2-STAT3 pathway and actin polymerization as potential therapeutic targets for drug-resistant, AIP-mutant pituitary tumors. Presentation: Saturday, July 12, 2025