Novel genetic dependencies in VRK2 methylated glioblastoma multiforme

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Abstract Glioblastoma multiforme (GBM) affects 10,000 Americans each year and is one of the most common and deadly brain cancers, with a median overall survival of 12-14 months from diagnosis. Treatment consists of a surgical resection, followed by chemo-radiation and further rounds of chemotherapy. In particular, patients whose tumors harbor MGMT methylation exhibit better responses to temozolomide (TMZ). Despite advances in care, few patients survive more than 5 years, and new treatments are desperately needed. We have created and interrogated the Cancer Dependency Map (www.depmap.org) and have discovered that a subset of GBM cell lines require VRK1 for proliferation and survival. Cancer cell lines that depend on VRK1 exhibit methylation and down-regulation of VRK2, a kinase involved in the DNA damage response and mitotic chromosome segregation. In the TCGA GBM cohort, approximately 15% of patients show decreased expression of VRK2. We propose to confirm VRK1 dependency in cancer cell lines and patient-derived GBM organoids with VRK2 methylation, and will determine whether VRK1 loss leads to defects in chromosome segregation and DNA damage response. In parallel, we will use a global phospho-proteomic approach to discover other druggable, signaling pathways affected by VRK2 methylation. Taken together, these studies will credential VRK1 as a target in GBM that exhibit VRK2 methylation and form the foundation for drug development efforts focused on the VRK family of kinases.