CNSC-36. VRK1 IS A PARALOG SYNTHETIC LETHAL TARGET IN VRK2-METHYLATED GLIOBLASTOMA. (14th November 2022)

• Record Type: Journal Article
• Authors: Shields, Julie; Meier, Samuel; Bandi, Madhavi; Ferdinez, Maria Dam; Engel, Justin; Mulkearns-Hubert, Erin; Hajdari, Nicole; Shen, Binzhang; Hubert, Christopher; Mitchell, Kelly; Zhang, Wenhai; Zhao, Shan-chuan; Bejnood, Alborz; Zhang, Minjie; Sjin, Robert Tjin Tham; Wilker, Erik; Lathia, Justin; Andersen, Jannik; Chen, Yingnan; Li, Fang; Weber, Barbara; Huang, Alan; Emmanuel, Natasha
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 7
• Page Start: vii29
• Page End: vii30
• Publication Date: 2022-11-14
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac209.116
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: 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-methylated GBM cell lines and patient-derived models was lethal and resulted 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, 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 VRK2 expression. Knockdown of VRK1 led 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.