Abstract 4323: Deletion of the lipid kinase PIKfyve in Kras-driven pancreatic genetically engineered mouse model
Authors: Sarah N. Yee, Xia Jiang, Caleb Cheng, Ahmet Korkaya, Rahul Mannan, Rohit Mehra, Yuanyuan Qiao, Arul M. Chinnaiyan
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) accounts for 95% of all pancreatic cancers and, as one of the most lethal cancers, has a five-year survival rate of approximately 6%. Autophagic processes have been reportedly elevated in PDAC; thus, the inhibition of autophagy leads to decreased tumor growth. Autophagic processes are catabolic mechanisms that recycle cellular components. Cells in stressful conditions, such as starvation, have elevated autophagy to redistribute energy to sustain cell survival; however, this can also lead to cell death when attempts to maintain cell viability fail. In addition, autophagy is known to promote immune evasion by tumors and cancer progression and appears to be required for the optimal development of PDAC. The lipid kinase PIKfyve converts phosphatidylinositol-3-phosphate to phosphatidylinositol 3,5-bisphosphate and is required in the late stage of the autophagic pathway. Blocking PIKfyve disrupts autophagic processes. However, the role of PIKfyve in PDAC development has not been fully understood. We investigated the role of PIKfyve in the progression of PDAC using a genetically engineered mouse model. Given the poor clinical outcomes of pharmacological inhibition of autophagy by chloroquine, we have evaluated the PIKfyve inhibitor ESK981 in the context of PDAC progression. Methods: The pancreatic-specific deletion of PIKfyve was established on a Kras G12D, Tp53 R172H, and p48 Cre (KPC) or Kras G12D and p48 Cre (KC) background. The ratio of pancreatic mass to body weight was monitored at various time points. Histopathology evaluations were conducted based on hematoxylin and eosin staining and immunohistochemistry of cytokeratin 19 staining. Pharmacological inhibition of PIKfyve was performed on KPC mice using ESK981 monotherapy. Four weeks after vehicle or ESK981 treatment, pancreatic tissues were collected intact and weighed. Histopathology evaluations were performed to evaluate the lesion. Conclusion: We demonstrated that the deletion of PIKfyve in pancreatic tissue significantly reduces the pancreatic mass weight compared to the PIKfyve wildtype counterpart and is coupled with less pancreatic intraepithelial neoplasia (PanIN) and PDAC development in KPC and KC mice. Compared to the vehicle treatment, pharmacological inhibition of PIKfyve by ESK981 on KPC mice resulted in a significant increase in the percentage of normal pancreatic tissue and reduced pancreatic lesion development. Citation Format: Sarah N. Yee, Xia Jiang, Caleb Cheng, Ahmet Korkaya, Rahul Mannan, Rohit Mehra, Yuanyuan Qiao, Arul M. Chinnaiyan. Deletion of the lipid kinase PIKfyve in Kras-driven pancreatic genetically engineered mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4323.