Abstract 2147: Synthetic lethality of VRK1 in VRK2-methylated cancers

Abstract Paralogs are a source of synthetic lethal interactions which lend themselves to novel bio-marker linked targeted therapeutics. From genome-wide essentiality measurements in over 900 cancer cell lines, we find VRK1 dependency in VRK2-methylated adult and pediatric gliomas and neuroblastomas. VRK2 methylation was mainly seen in IDH-mutant gliomas and H3.3-G34R-mutant DIPG. Knockout of VRK2 was able to sensitize cells to VRK1 knockout. Overexpression of kinase-active but not kinase inactive VRK2 rescued VRK1 knockout. Global phosphoproteomics in VRK1 and VRK2 knockout cells demonstrate increased phosphorylation of targets involved with DNA damage and decreased phosphorylation of nuclear membrane targets. VRK1 and VRK2 were found to phosphorylate BANF1, which is involved in nuclear membrane re-formation during mitosis. Taken together, we show that VRK1 is a viable target in VRK2-methylated adult and pediatric gliomas, and neuroblastomas. Citation Format: Jonathan So, Nathaniel Mabe, Bernhard Englinger, Jason Kwon, Brian Shim, Mariella Filbin, Kimberly Stegmaier, William Hahn. Synthetic lethality of VRK1 in VRK2-methylated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2147.