MET kinase fusions in pediatric glioblastoma

摘要 高级别胶质瘤（HGG）是儿童中最致命的恶性原发性脑肿瘤， 无法用现有疗法治愈。寻找驱动儿童HGG形成和进展的突变 （pHGG），我们对超过25种肿瘤进行了基因组学表征，并鉴定了MET和ALK中的融合突变， 受体酪氨酸激酶。最近的综合分析表明，RTK融合被发现在高达40%的 pHGG中最常见的是MET和ALK融合，在超过10%的pHGG中发现。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N-末端激酶结构域， 在神经胶质干/祖细胞中通常高度表达的其他蛋白质区域，表明 MET融合体可能由于发育程序而过度表达。结果表明，RTK 融合物，如MET融合物，产生能够转化神经干细胞的组成型活性激酶 pHGG样肿瘤FDA批准的小分子酪氨酸激酶抑制剂（TKI）存在，其穿透细胞膜。 血脑屏障可能使MET和ALK融合以及其他RTK融合的pHGG患者受益，以及 这些TKI正在RTK融合患者中进行试验。尽管最初 在缓解后，MET融合pHGG患者迅速发展为耐药继发性肿瘤。因此，我们使用 我们的实验MET融合模型，包括患者来源的pHGG肿瘤干细胞和异种移植物， 以及免疫活性pHGG小鼠模型，以发现TKI耐药机制。已经，我们 初步研究表明TKI药物中存在细胞固有的先天免疫和炎性细胞因子信号传导 在具有MET融合物的pHGG细胞中耐受性和抗性的出现。去发现和研究抗药性 MET和其他RTK融合在pHGG中的机制，我们提出了两个目标：1）检查相互作用 RTK融合、RTK激酶抑制剂和炎性细胞因子信号通路及其效应物之间的关系 使用我们的稳健MET融合模型在体外和体内在脑中进行，以及2）测试RTK激酶之间的协同作用 抑制剂和炎症途径抑制。我们将使用 RTK融合pHGG的其他模型，以确定我们的观察结果是否可在pHGG中推广， RTK融合。我们的研究结果可能会导致新的组合精密处理的发展 pHGG的策略。

ABSTRACT High grade gliomas (HGGs), the most deadly malignant primary brain tumors in children, and are incurable with current therapies. To find mutations that drive formation and progression of pediatric HGGs (pHGGs), we genomically characterized over 25 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 and ALK fusions, found in more than 10% of pHGGs. 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 quickly developed resistant secondary tumors. Therefore, we are using our experiments MET fusion models, which include patient-derived pHGG tumor stem cells and xenografts as well as immunocompetent pHGG mouse models, to discover TKI resistance mechanisms. Already, our preliminary studies implicate cell-intrinsic innate immunity and inflammatory cytokine signaling in TKI drug tolerance and emergence of resistance among pHGG cells with MET fusions. To discover and study resistance mechanisms for MET and other RTK fusions in pHGG, we propose to two aims to 1) examine interactions between RTK fusions, RTK kinase inhibitors, and inflammatory cytokine signaling pathways and their effectors in vitro and in vivo in the brain using our robust MET fusion models, and to 2) test synergy between RTK kinase inhibitors and inflammatory pathway inhibition using pharmacologic and genetic approaches. We will use additional models of RTK fusions pHGGs to determine if our observations are generalizable among pHGGs with RTK fusions. The results of our research may lead to development of new combination precision treatment strategies for pHGG.