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

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 the...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2022-11, Vol.24 (Supplement_7), p.vii29-vii30
Main 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
Format: Article
Language:English
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Summary: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.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/noac209.116