Abstract B023: Repurposing of the SP/NK1R-complex inhibitor aprepitant in hepatopancreatic malignancies

Abstract Background: The neurokinin-1 receptor (NK1R) complex, activated by Substance P (SP), has emerged as a promising target. SP promotes cell growth, whereas its antagonist, Aprepitant (AP), used clinically for chemotherapy-induced nausea, has demonstrated anti-tumor activity. However, further insight on the anti-tumoral mechanisms after antagonistic targeting of the complex are required. Methods: We conducted bioinformatical analysis of public as well as own RNAseq data. Assays to assess cell proliferation and cell viability (MTT, scratch assays, colony formation) as well as apoptosis and autophagy were carried out. Metabolic changes were detected by SeaHorse analysis, ROS, NAD+/NADH, and MitoTracker. Results: Patient-derived organoid cultures showed reduced spheroid formation and altered morphology following AP treatment, while SP enhanced spheroid formation. SP promoted proliferation via Rho-kinase-dependent mechanisms and activated the ERK signaling pathway, with AP slightly reducing pERK levels. Further analyses revealed that AP induces apoptosis signaling without subsequent DNA fragmentation. Annexin V/PI staining indicated apoptosis induction after 24 hours, while subG1 analysis suggested a blockade in the apoptosis cascade. Prolonged AP exposure led to necrosis, which was mitigated by co-treatment with N-acetylcysteine. Western blot analysis confirmed caspase-9 and -3 activation but showed no PARP cleavage, likely due to high expression of inhibitors of apoptosis proteins (IAPs), such as XIAP. Conclusion: In conclusion, AP exhibits antiproliferative and cytotoxic effects in pancreatic tumor cells, potentially disrupting an autocrine/paracrine SP-NK1R feedback loop and altering metabolic resilience. Future studies should explore metabolic stress responses and investigate whether co-treatment could overcome incomplete apoptosis activation. Citation Format: Matthias Ilmer, Maximilian Viessmann, Bernhard Renz, Frank Braun, Jens Werner. Repurposing of the SP/NK1R-complex inhibitor aprepitant in hepatopancreatic malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B023.