VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system

Jonathan So, Nathaniel W. Mabe, Bernhard Englinger, Kin Hoe Chow, Sydney M. Moyer, Smitha Yerrum, Maria C. Trissal, Joana G. Marques, Jason J. Kwon, Brian Shim, Sangita Pal, Eshini Panditharatna, Thomas Quinn, Daniel A. Schaefer, Daeun Jeong, David L. Mayhew, Justin Hwang, Rameen Beroukhim, Keith L. Ligon, Kimberly StegmaierMariella G. Filbin, William C. Hahn

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Article numbere158755
JournalJCI Insight
Issue number19
StatePublished - Oct 10 2022

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Copyright: © 2022, So et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.


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