@article{10.1172/jci.insight.158755, author = {Jonathan So AND Nathaniel W. Mabe AND Bernhard Englinger AND Kin-Hoe Chow AND Sydney M. Moyer AND Smitha Yerrum AND Maria C. Trissal AND Joana G. Marques AND Jason J. Kwon AND Brian Shim AND Sangita Pal AND Eshini Panditharatna AND Thomas Quinn AND Daniel A. Schaefer AND Daeun Jeong AND David L. Mayhew AND Justin Hwang AND Rameen Beroukhim AND Keith L. Ligon AND Kimberly Stegmaier AND Mariella G. Filbin AND William C. Hahn}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {VRK1 as a synthetic lethal target in VRK2 promoter–methylated cancers of the nervous system}, year = {2022}, month = {10}, volume = {7}, url = {https://insight.jci.org/articles/view/158755}, abstract = {Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter–methylated adult and pediatric gliomas and neuroblastomas.}, number = {19}, doi = {10.1172/jci.insight.158755}, url = {https://doi.org/10.1172/jci.insight.158755}, }