RT Journal Article SR Electronic T1 VRK1 is a Paralog Synthetic Lethal Target in VRK2-methylated Glioblastoma JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.12.30.474571 DO 10.1101/2021.12.30.474571 A1 Julie A. Shields A1 Samuel R. Meier A1 Madhavi Bandi A1 Maria Dam Ferdinez A1 Justin L. Engel A1 Erin E. Mulkearns-Hubert A1 Nicole Hajdari A1 Kelly Mitchell A1 Wenhai Zhang A1 Shan-chuan Zhao A1 Minjie Zhang A1 Robert Tjin Tham Sjin A1 Erik Wilker A1 Justin D. Lathia A1 Jannik N. Andersen A1 Yingnan Chen A1 Fang Li A1 Barbara Weber A1 Alan Huang A1 Natasha Emmanuel YR 2022 UL http://biorxiv.org/content/early/2022/01/01/2021.12.30.474571.abstract AB Synthetic lethality — a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone — can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interaction by virtue of their redundant functions. Here we demonstrate a paralog-based synthetic lethality by targeting Vaccinia-Related Kinase 1 (VRK1) in Vaccinia-Related Kinase 2 (VRK2)-methylated glioblastoma (GBM). VRK2 is silenced by promoter methylation in approximately two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells results in decreased activity of the downstream substrate Barrier to Autointegration Factor (BAF), a regulator of post-mitotic nuclear envelope formation. VRK1 knockdown, and thus reduced BAF activity, causes nuclear lobulation, blebbing and micronucleation, which subsequently results in G2/M arrest and DNA damage. The VRK1-VRK2 synthetic lethal interaction is dependent on VRK1 kinase activity and is rescued by ectopic VRK2 expression. Knockdown of VRK1 leads to robust tumor growth inhibition in VRK2-methylated GBM xenografts. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.Competing Interest StatementJ.A.S., S.R.M., M.B., M.D.F., J.L.E., W.Z., S.Z., M.Z., R.T.T.S., A.H., B.W. J.N.A, E.W., Y.C., F.L. and N.E are employees and shareholders of Tango Therapeutics