Novel genetic dependencies in VRK2 methylated glioblastoma multiforme

摘要 多形性胶质母细胞瘤（GBM）每年影响10，000名美国人，是最常见和最常见的肿瘤之一。 致命的脑癌，从诊断开始的中位总生存期为12-14个月。治疗包括 手术切除，然后是化疗-放疗和进一步的化疗。特别是，患者 其肿瘤具有MGMT甲基化，对替莫唑胺（TMZ）表现出更好的反应。尽管取得了进展 在护理中，很少有患者存活超过5年，迫切需要新的治疗方法。 我们已经创建并查询了癌症依赖地图（www.depmap.org），并发现， GBM细胞系的一个子集需要VRK 1来增殖和存活。依赖于VRK 1的癌细胞系 显示VRK 2的甲基化和下调，VRK 2是一种参与DNA损伤反应和有丝分裂的激酶， 染色体分离在TCGA GBM队列中，约15%的患者表现出降低的 VRK 2的表达。 我们建议用VRK 2证实癌细胞系和患者来源的GBM类器官中的VRK 1依赖性 甲基化，并将决定VRK 1的损失是否会导致染色体分离和DNA缺陷 损伤响应与此同时，我们将使用一种全局磷酸化蛋白质组学方法来发现其他可药用的， 受VRK 2甲基化影响的信号通路。总之，这些研究将证明VRK 1是一种 靶向表现出VRK 2甲基化的GBM，并形成药物开发工作的基础， VRK激酶家族。

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.