MET kinase fusions in pediatric glioblastoma

摘要 高级别胶质瘤（HGG）是儿童最致命的原发性恶性脑肿瘤，是无法治愈的 目前的疗法。为了找到驱动儿科HGG（pHGG）形成和进展的突变，我们 基因组特征的患者肿瘤，我们确定了MET和ALK受体的融合突变， 酪氨酸激酶最近的综合分析表明，RTK融合在高达40%的pHGG中发现， 其中最常见的是MET、ALK和NTRK融合。我们和其他人的数据表明，对于许多RTK， 融合，其中C-末端激酶结构域融合到正常情况下 在神经胶质干/祖细胞中高度表达，表明MET融合体可能作为一种免疫调节剂过度表达。 发展计划的后果。我们的研究结果表明，RTK融合，如MET融合，创造 能够将神经干细胞转化为pHGG样肿瘤的组成型活性激酶。fda批准 小分子酪氨酸激酶抑制剂（TKI）存在，其穿透血脑屏障， 患有MET和ALK融合以及其他RTK融合的pHGG患者，这些TKI正在 在研究基础上接受RTK融合的患者。然而，尽管有初步反应，MET融合pHGG 患者可能会产生耐药肿瘤。因此，为了发现TKI耐药机制，我们创建了 MET和ALK融合肿瘤的实验免疫活性小鼠pHGG模型。已经，我们 初步研究表明，细胞固有的先天免疫和炎症细胞因子信号通路在药物治疗中起着重要作用。 在具有MET融合物的pHGG细胞中的耐受性和抗性。发现和研究抗药性机制 为了确定生物性别是否影响pHGG与RTK融合，我们提出了两个目标：1）检查 用RTK融合物在pHGG中表达和激活先天免疫途径，以及2）检查性别 先天免疫途径在具有RTK融合的pHGG中起作用的差异。我们的研究结果可能 从而开发出pHGG新的组合精确治疗策略。 1

ABSTRACT High grade gliomas (HGGs), the most deadly malignant primary brain tumors in children, are incurable with current therapies. To find mutations that drive formation and progression of pediatric HGGs (pHGGs), we genomically characterized patient tumors, and we identified fusion mutations in the MET and ALK receptor tyrosine kinases. Recent comprehensive analyses show that RTK fusions are found in up to 40% of pHGGs, and among the most common are MET, ALK, and NTRK fusions. Our and others’ data show that for many RTK fusions, in which the C-terminal kinase domain is fused to N-terminal regions of other proteins that are normally highly expressed in neuro-glial stem/progenitor cells, indicating that MET fusions are likely overexpressed as a consequence of developmental programs. Our results show that RTK fusions, such as the MET fusions, create constitutively active kinases capable of transforming neural stem cells into pHGG-like tumors. FDA-approved small molecule tyrosine kinase inhibitors (TKIs) exist that penetrate the blood-brain barrier that may benefit pHGG patients with MET and ALK fusions as well as other RTK fusions, and these TKIs are being tested in patients with RTK fusions on an investigational basis. However, despite initial responses, MET fusion pHGG patients can develop resistant tumors. Therefore, to discover TKI resistance mechanisms, we have created our experimental immunocompetent mouse pHGG models for tumors with MET and ALK fusions. Already, our preliminary studies implicate cell-intrinsic innate immunity and inflammatory cytokine signaling pathways in drug tolerance and resistance among pHGG cells with MET fusions. To discover and study resistance mechanisms and to determine if biological sex affects how pHGGs with RTK fusions, we propose to two aims to 1) examine expression and activation of innate immunity pathways in pHGGs with RTK fusions and 2) examine sex differences in innate immunity pathways function in pHGGs with RTK fusions. The results of our research may lead to development of new combination precision treatment strategies for pHGG. 1