Abstract 4137: Investigating VRK1 inhibition as an anti-cancer therapy for pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a aggressive and often a lethal form of exocrine pancreatic cancer with a 5-year survival rate of 12%. Current PDAC therapeutics are ineffective and highly toxic, leading to a variety of harsh side effects that greatly reduce patient quality of life. This low quality of life highlights the need for new approaches. This study investigates the potential of inducing nuclear envelope instability in PDAC cells through inhibition of Vaccinia-Related Kinase 1 (VRK1). Previous studies in the Vaughan lab have demonstrated that the knock down of VRK1 reduces BAF phosphorylation, reduces BAF/Lamin A interaction, and leads to nuclear blebbing. Evidence also suggests that nuclear blebbing leads to DNA leakage and activation of the cGAS-STING pathway and cellular senescence. However, it remains unclear what stage of the cell cycle is inhibited by VRK1 inhibition. To determine when this phenomenon occurs, we synchronized Cos7 cells using a thymidine and nocodazole block and treated with VRK1-IN-1, a potent VRK1 inhibitor. To determine if VRK1 inhibition affects a certain stage of mitosis, cells were synchronized and stained for tubulin and Lamin A. We observed that VRK1-IN-1 does not affect a specific stage of the cell cycle. Here we developed a protocol for measuring the effect of VRK1 inhibitors on mitosis and the cell cycle. This protocol will serve as a launching point to validate the discovery of VRK1 inhibitors from a 12,000-compound kinase assay screen. Elucidation and understanding of when VRK1 inhibition activate/induces the cGAS-STING pathway and cellular senescence, may provide the rational for to pursuing of VRK1 inhibitors as novel therapeutics for the treatment of PDAC. Citation Format: Kun Yuan Chu, Yaning Xi, Shelby Schwarz, Kevin T. Vaughan. Investigating VRK1 inhibition as an anti-cancer therapy for pancreatic ductal adenocarcinoma [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 4137.