VRK1 is a Synthetic Lethal Target in VRK2-deficient Glioblastoma

Julie A Shields, Samuel R Meier, Madhavi Bandi, Erin E Mulkearns-Hubert, Nicole Hajdari, Maria Dam Ferdinez, Justin L Engel, Daniel J Silver, Binzhang Shen, Wenhai Zhang, Christopher G Hubert, Kelly Mitchell (+13 others)
2022
Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic lethal interactions by virtue of their redundant functions. Here we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of vaccinia-related
more » ... e 2 (VRK2), which is silenced by promoter methylation in approximately two-thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2/M arrest and DNA damage. The VRK1-VRK2 synthetic lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.
doi:10.1158/0008-5472.can-21-4443 pmid:36069976 pmcid:PMC9627132 fatcat:6wv7m4ug6rd57e3xdvw4bofp7q