Abstract P182: VRK1 is a novel synthetic lethal target in VRK2-methylated glioblastoma

Synthetic lethality — the genetic interaction that causes cell death when two genetic deficiencies co-occur but cell survival when each deficiency occurs alone — can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interactions by virtue of their redundant function in the cell. Here we demonstrate a paralog synthetic lethality by targeting VRK1 in VRK2-methylated glioblastoma multiforme (GBM). VRK2 is silenced by methylation in about two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells leads to cell death via cell cycle arrest in G2M and subsequent DNA damage. The lethality is dependent on the kinase activity of VRK1 and is rescued by ectopic VRK2 expression. Knockdown of VRK1 leads to robust tumor growth inhibition in VRK2-methylated glioblastoma xenografts in vivo. These results suggest that inhibiting VRK1 kinase activity could be a viable cancer therapeutic in VRK2-methylated glioblastoma. Citation Format: Julie Shields, Samuel R. Meier, Justin Engel, Madhavi Bandi, Maria L. Dam Ferdinez, Wenhai Zhang, Shan-chuan Zhao, Minjie Zhang, Ashley Choi, Yi Yu, Xuewen Pan, Brian McMillan, Brett Williams, Robert Tjin Tham Sjin, Douglas Whittington, Erik Wilker, Alan Huang, Fang Li, Natasha Emmanuel. VRK1 is a novel synthetic lethal target in VRK2-methylated glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P182.