Abstract 3872: Fatty acid synthase inhibition to prevent metastatic colonization by pancreatic neuroendocrine tumor cells

Abstract Introduction: Pancreatic neuroendocrine tumors (pNETs) are among the most frequently occurring neuroendocrine neoplasms. At the time of diagnosis most patients have extensive metastatic disease and are not candidates for curative surgical resection. Therefore, identification of pathways that promote pNET metastasis is critical for developing targeted therapies to prevent cancer cells from colonization of parenchymal organs. The purpose of this study was to determine whether fatty acid synthase (FASN) inhibition can be used as a target against metastatic spread of pNETs. Methods: Expression of FASN was evaluated in pancreatic neuroendocrine primary and metastatic tumors and scored by a pathologist. Neutral lipid droplet levels in BON, QGP-1 and NT-3 cell lines were determined with BODIPY 493/503 staining. Clonogenic and SRB assays were used to evaluate cytotoxic effects of FASN inhibition by TVB-3664 in QGP-1 and BON pNET cell lines. Western blot analysis was used to determine levels of cleaved PARP and cyclin D1 after FASN inhibition. FASN knockdown was used to delineate the effects of FASN downregulation on proliferation and lipid synthesis. Intravenous (iv) and intraperitoneal (ip) injections of BON GFP-Luc cells were used to establish lung metastasis and peritoneal carcinomatosis, respectively. Results: FASN expression was determined at the maximum scores of 6 and 5 in 98% of patient samples. Highest levels of neutral lipid droplets were observed in the BON cell line. BON and QGP-1 cells were treated with TVB-3664 in either complete media with fatty acids (FA+) or complete media prepared with fatty acid depleted (FA-) FBS. Treatment with TVB-3664 resulted in significant inhibition of QGP-1 cell proliferation and cyclin D1 expression in both FA+ and FA- conditions. Depletion of extracellular FA enhanced the effect of TVB-3664 therapy on NET cells. FASN inhibition with TVB-3634 suppressed pNET cell proliferation and colony formation. Knockdown of FASN resulted in over 90% suppression of lung metastasis colonization. Pretreatment of BON GFP-luc cells with FASN inhibitor TVB-3664 before iv or ip injections also significantly suppressed lung metastasis colonization and peritoneal carcinomatosis. Conclusions: Our study demonstrated high expression levels of FASN in pNET patient samples and cell lines. QGP cell viability was significantly decreased with FASN inhibition even in the presence of extracellular lipids. FASN inhibition alone in BON cells had only a minimal effect on cell viability and required depletion of extracellular lipids to achieve a significant decrease in cell viability. Despite minimal effects on BON cell viability, pretreatment with TVB-3664 in FA+ conditions had a pronounced effect on lung colonization and peritoneal carcinomatosis. These data demonstrate an essential role of de novo lipid synthesis in the pNET metastatic cascade - colonization of parenchymal organs. Citation Format: Piotr Rychahou, Benjamin M. Evers, Yekateriza Zaytseva, Courtney M. Townsend, B. Mark Evers. Fatty acid synthase inhibition to prevent metastatic colonization by pancreatic neuroendocrine tumor 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 3872.