CNSC-36. VRK1 IS A PARALOG SYNTHETIC LETHAL TARGET IN VRK2-METHYLATED GLIOBLASTOMA

Abstract Synthetic lethality — a genetic interaction that results in cell death when two deficiencies co-occur but not either deficiency occurs alone can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal by virtue their redundant functions. Here we demonstrate paralog-based targeting Vaccinia-Related Kinase 1 (VRK1) 2 (VRK2)-methylated glioblastoma (GBM). VRK2 silenced promoter methylation approximately two-thirds GBM, an aggressive with few available targeted therapies. Genetic knockdown VRK1 VRK2-methylated GBM lines and patient-derived models was resulted decreased activity downstream substrate Barrier to Autointegration Factor (BAF), regulator post-mitotic nuclear envelope formation. knockdown, thus reduced BAF activity, caused lobulation, blebbing micronucleation, which subsequently G2/M arrest DNA damage. The VRK1-VRK2 dependent on kinase rescued ectopic expression. Knockdown led robust tumor growth inhibition xenografts. These indicate inhibiting could viable therapeutic strategy GBM.