Abstract PO-007: PRMT5 inhibition sensitizes pancreatic cancer to gemcitabine in orthotopic and metastatic murine models

Abstract

Abstract Purpose: The purpose of this study was to investigate protein arginine methyltransferase 5 (PRMT5) as a therapeutic target in combination with gemcitabine for pancreatic cancer in preclinical models. Procedures: In an orthotopic xenograft model, PRMT5 wild-type (WT) or knockout (KO) mPanc96 cells were injected into the pancreata of athymic nude mice. Mice were randomized to control or gemcitabine (100 mg/kg) arms. Tumor volume was measured with magnetic resonance imaging (MRI) at 21, 28, and 35 days post-injection. In a liver metastasis model, PRMT5 WT or KO mPanc96 cells were injected into the spleens of athymic nude mice followed by splenectomy after 10 minutes. Mice were randomized to control or gemcitabine (100 mg/kg) arms. Metastatic tumor burden within the liver was measured with in vivo bioluminescence imaging twice weekly for 19 days post-injection. Relative bioluminescence was calculated relative to post-injection day 2. Results: In the orthotopic model, untreated PRMT5 KO tumors exhibited a 46% reduction in tumor volume compared to untreated PRMT5 WT tumors (959 mm−3 vs. 1766 mm−3, p=0.009). Furthermore, gemcitabine-treated PRMT5 KO tumors exhibited a 30% reduction in tumor volume compared to gemcitabine-treated PRMT5 WT tumors (405 mm−3 vs. 579 mm−3, p=0.046). Compared to untreated PRMT5 WT tumors, gemcitabine-treated PRMT5 KO tumors exhibited a 77% reduction in tumor volume (405 mm−3 vs. 1766 mm−3, p=<0.001). In the liver metastasis model, untreated PRMT5 KO cells exhibited a 45% reduction in relative bioluminescence compared to untreated PRMT5 WT metastases (83.3 vs. 152.8, p=0.02). Additionally, gemcitabine-treated PRMT5 KO metastases exhibited a 52% reduction in relative bioluminescence compared to gemcitabine-treated PRMT5 WT metastases (17.2 vs. 36.0, p=0.02). Compared to untreated PRMT5 WT metastases, gemcitabine-treated PRMT5 KO metastases exhibited an 89% reduction in liver tumor burden (17.2 vs. 152.8, p=<0.001). Conclusions: PRMT5 genetic depletion significantly reduces pancreatic cancer growth in murine models of orthotopic growth and liver metastasis. Additionally, PRMT5 depletion improves gemcitabine response in these models. PRMT5 is a possible therapeutic target in pancreatic cancer treatment that necessitates further investigation. Citation Format: William J. Kane, Sara J. Adair, Sarbajeet Nagdas, Denis Liu, Xiaolong Wei, Mazhar Adli, Todd W. Bauer. PRMT5 inhibition sensitizes pancreatic cancer to gemcitabine in orthotopic and metastatic murine models [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-007.