TY - JOUR T1 - VRK1 is a Paralog Synthetic Lethal Target in VRK2-methylated Glioblastoma JF - bioRxiv DO - 10.1101/2021.12.30.474571 SP - 2021.12.30.474571 AU - Julie A. Shields AU - Samuel R. Meier AU - Madhavi Bandi AU - Maria Dam Ferdinez AU - Justin L. Engel AU - Erin E. Mulkearns-Hubert AU - Nicole Hajdari AU - Kelly Mitchell AU - Wenhai Zhang AU - Shan-chuan Zhao AU - Minjie Zhang AU - Robert Tjin Tham Sjin AU - Erik Wilker AU - Justin D. Lathia AU - Jannik N. Andersen AU - Yingnan Chen AU - Fang Li AU - Barbara Weber AU - Alan Huang AU - Natasha Emmanuel Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/01/2021.12.30.474571.abstract N2 - 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 ER -